edoxaban and Stroke

Several studies have evaluated the economic evaluation of a group of medications known as novel oral anticoagulant drugs (NOACs) in recent years. The aim of this study is to review and systematically analyze the cost-utility studies results of warfarin compared with other NOAC drugs in atrial fibrillation patients.. A systematic review was performed to identify all studies evaluating the NOAC medications in comparison with warfarin. For this purpose, PubMed, Cochrane Library, ISI Web of Science, and Scopus were searched from 2013 to 2022. Articles were independently screened with inclusion criteria, and full texts were reviewed. First, the Consolidated Health Economic Evaluation Reporting Standards checklist was used to evaluate the quality of the articles. Then, the costs and outcomes of the studies were analyzed, and findings were appraised critically.. A total of 84 costs-per-quality-adjusted life-year (QALY) cases were extracted from the studies in which the share of rivaroxaban, edoxaban, apixaban, and dabigatran were 31%, 13%, 29%, and 27%, respectively. The median cost per QALY of rivaroxaban, edoxaban, apixaban, and dabigatran was 21 910$/QALY, 22 096$/QALY, 17 765$/QALY, and 24 161$/QALY, respectively. Subgroup analysis based on perspective showed that dabigatran had the highest incremental cost-effectiveness ratio (ICER) and edoxaban had the lowest ICER value. Edoxaban and apixaban had the highest and the lowest cost per QALY from an insurance perspective, respectively.. Despite the differences and variations in the economic evaluation studies of NOAC drugs, these drugs have shown acceptable cost-effectiveness in developed and developing countries. Among NOAC drugs, apixaban has the lowest ICER and the highest cost-effectiveness.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Cost-Benefit Analysis; Dabigatran; Humans; Rivaroxaban; Stroke; Warfarin

Direct oral anticoagulants (DOAC) are progressively replacing vitamin K antagonists in the prevention of thromboembolism in patients with atrial fibrillation. However, their real-world clinical outcomes appear to be contradictory, with some studies reporting fewer and others reporting higher complications than the pivotal randomized controlled trials. We present the results of a clinical model for the management of DOACs in real clinical practice and provide a review of the literature.. The MACACOD project is an ongoing, observational, prospective, single-center study with unselected patients that focuses on rigorous DOAC selection, an educational visit, laboratory measurements, and strict follow-up.. A total of 1,259 patients were included. The composite incidence of major complications was 4.93% py in the whole cohort vs 4.49% py in the edoxaban cohort. The rate of all-cause mortality was 6.11% py for all DOACs vs 5.12% py for edoxaban. There weren't differences across sex or between Edoxaban reduced or standard doses. However, there were differences across ages, with a higher incidence of major bleeding complications in patients >85 years (5.13% py vs 1.69% py in <75 years).. We observed an incidence of serious complications of 4.93% py, in which severe bleeding predominated (3.65% py). Considering our results, more specialized attention seems necessary to reduce the incidence of severe complications and also a more critical view of the literature. Considering our results, and our indirect comparison with many real-world studies, more specialized attention seems necessary to reduce the incidence of severe complications in AF patients receiving DOACs.

Topics: Administration, Oral; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Humans; Prospective Studies; Pyridines; Stroke

Direct oral anticoagulants (DOACs) are associated with bleeding. Patients often stop taking DOACs due to non-major bleeding, which may lead to stroke recurrence. We aimed to determine the risk of non-major bleeding using different DOACs to prevent strokes in atrial fibrillation (AF).. A systematic search of four databases (PubMed, EMBASE, Web of Science, and Cochrane Library) was performed to identify randomized controlled trials (RCTs) reporting non-major bleeding events in patients taking DOACs or vitamin K antagonists (VKAs). In this frequency-based network meta-analysis, odds ratios and 95% confidence intervals were used for reporting. Based on the surface under the cumulative ranking curves (SUCRA), the relative ranking probability of each group was generated.. Nineteen randomized controlled trials (RCTs) (involving 85,826 patients) were included. For clinically relevant non-major bleeding, the risk for bleeding was lowest for apixaban (SUCRA, 93.9), followed by that for VKAs (SUCRA, 47.7), dabigatran (SUCRA, 40.3), rivaroxaban (SUCRA, 35.9), and edoxaban (SUCRA, 32.2). The minor bleeding safety of DOACs was ranked from highest to lowest as follows: apixaban (SUCRA, 78.1), edoxaban (SUCRA, 69.4), dabigatran (SUCRA, 48.8), and VKAs (SUCRA, 3.7).. Based on current evidence, for stroke prevention in patients with AF, the safest DOAC is apixaban in terms of non-major bleeding. This suggests that apixaban may have a lower risk of non-major bleeding than other anticoagulants and may help provide some clinical reference for choosing a more appropriate drug for the patient.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Fibrinolytic Agents; Hemorrhage; Humans; Network Meta-Analysis; Rivaroxaban; Stroke; Vitamin K

Although older patients with atrial fibrillation are at heightened risk of thromboembolic and bleeding events, their optimal treatment choice remains uncertain.. This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched the PubMed, EMBASE, and Cochrane databases for randomized controlled trials that compared thromboembolic or bleeding outcomes between a direct oral anticoagulant (DOAC) and a vitamin K antagonist (VKA) and reported outcomes for patients aged ≥75 years with atrial fibrillation. The efficacy outcome was the composite of stroke and systemic embolism. Safety outcomes included major bleeding, any clinically relevant bleeding, and intracranial hemorrhage. Each DOAC and VKA was compared pairwise in a network meta-analysis. High- and low-dose regimens and factor IIa and Xa inhibitors were also compared. Seven randomized controlled trials were included in the analysis. Stroke and systemic embolism risks did not differ significantly among DOACs. There were no significant differences in major bleeding between each DOAC and VKA. Intracranial hemorrhage risk was significantly lower with dabigatran, apixaban, and edoxaban than with VKA and rivaroxaban, which had similar risks. High-dose regimens led to lower risks of stroke or systemic embolism compared with VKA and low-dose regimens, with both doses having similar bleeding risks.. In patients aged ≥75 years with atrial fibrillation, DOACs were associated with fewer thromboembolic events compared with VKA, whereas dabigatran, apixaban, and edoxaban were associated with lower risks of intracranial hemorrhage compared with VKA and rivaroxaban.. URL: www.crd.york.ac.uk/prospero/. Unique identifier: CRD42022329557.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Embolism; Hemorrhage; Humans; Intracranial Hemorrhages; Network Meta-Analysis; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke

We aimed to determine the safety of direct oral anticoagulants (DOACs) for stroke prevention and treatment in patients with atrial fibrillation (AF).. A systematic search of four databases (PubMed, EMBASE, Web of Science, and Cochrane Library) was performed to identify randomized controlled trials (RCTs) reporting severe bleeding events in patients taking DOACs or vitamin K antagonists (VKAs). In this frequency-based network meta-analysis, odds ratios and 95% confidence intervals were used for reporting. Based on the surface under the cumulative ranking curves (SUCRA), the relative ranking probability of each group was generated.. Twenty-three RCTs met the inclusion criteria, and a total of 87,616 patients were enrolled. The bleeding safety of DOACs for stroke prevention and treatment in patients with AF was ranked from highest to lowest as follows: fatal bleeding: edoxaban (SUCRA,80.2), rivaroxaban (SUCRA,68.3), apixaban (SUCRA,48.5), dabigatran (SUCRA,40.0), VKAs (SUCRA,12.9); major bleeding: dabigatran (SUCRA,74.0), apixaban (SUCRA,71.5), edoxaban (SUCRA,66.5), rivaroxaban (SUCRA,22.7), VKAs (SUCRA,15.4); gastrointestinal bleeding: apixaban (SUCRA,55.9), VKAs (SUCRA,53.7), edoxaban (SUCRA,50.5), rivaroxaban (SUCRA,50.4), dabigatran (SUCRA,39.5); intracranial hemorrhage: dabigatran (SUCRA,84.6), edoxaban (SUCRA,74.1), apixaban (SUCRA,65.8), rivaroxaban (SUCRA,24.4), VKAs (SUCRA,1.1).. Based on current evidence, for stroke prevention and treatment in patients with AF, the most safe DOAC is edoxaban in terms of fatal bleeding; dabigatran in terms of major bleeding and intracranial hemorrhage and apixaban in terms of gastrointestinal bleeding. However, given the nature of indirect comparisons, more high-quality evidence from head-to-head comparisons is still needed to confirm them.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Factor Xa Inhibitors; Gastrointestinal Hemorrhage; Humans; Intracranial Hemorrhages; Network Meta-Analysis; Rivaroxaban; Stroke; Vitamin K

An optimal antithrombotic strategy for patients aged 80 years or older with atrial fibrillation (AF) remains elusive.. Using a systematic review with traditional and network meta-analysis, we investigated outcomes in AF patients ≥80 years treated with different antithrombotic strategies.. We searched eligible randomised controlled trials (RCTs) and observational studies from MEDLINE, EMBASE, Cochrane Library and Web of Science databases from inception to 16 December 2021. Research comparing treatment outcomes of novel oral anticoagulants (NOACs), aspirin, vitamin K antagonists (VKAs) or no oral anticoagulant/placebo therapy in patients ≥80 years with AF were included. Outcomes were stroke or systemic embolism (SSE), major bleeding, all-cause mortality, intracranial bleeding (ICH) and gastrointestinal bleeding. Traditional and network meta-analyses were performed. Net clinical benefit integrating SSE and major bleeding was calculated.. Fifty-three studies were identified for analysis. In the meta-analysis of RCTs, risk of SSE (risk ratio [RR]: 0.82; 95% confidence interval [CI]: 0.73-0.99) and ICH (RR: 0.38; 95% CI: 0.28-0.52) was significantly reduced when NOACs were compared with VKAs. Network meta-analysis of RCTs demonstrated that edoxaban (P-score: 0.8976) and apixaban (P-score: 0.8528) outperformed other antithrombotic therapies by showing a lower major bleeding risk and better net clinical benefit. Both traditional and network meta-analyses from RCTs combining with observational studies showed consistent results.. In patients aged 80 years or older with AF, NOACs have better outcomes than VKAs regarding efficacy and safety profiles. Edoxaban and apixaban may be preferred treatment options since they are safer than other antithrombotic strategies.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Fibrinolytic Agents; Hemorrhage; Humans; Network Meta-Analysis; Stroke

In the past decade, direct oral anticoagulants (DOACs) have transformed the world of anti-thrombotic therapy. Edoxaban is the most recently approved DOAC. Though intended for use primarily in stroke prevention, it has found applications in various other conditions including thromboembolic and peripheral arterial disease. This review aims to provide a detailed outline of the growing indications, evidence for use in special populations, pharmacogenetics and side-effect profile of edoxaban.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Humans; Pyridines; Stroke; Thiazoles

Atrial fibrillation (AF) is the most common type of arrhythmia. Warfarin reduces the incidence and mortality of strokes in patients with AF. Edoxaban reduces the bleeding risk in patients with AF. This study evaluates the efficacy and safety of edoxaban versus warfarin in preventing clinical events in patients with AF through a meta-analysis of randomized controlled trials (RCTs). RCTs were retrieved from medical literature databases. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated to compare the primary and safety endpoints. In total, five articles (10 trial comparisons) containing 24,836 patients were retrieved. Of these patients, 16,268 (65.5%) received edoxaban and 8,568 (34.5%) received warfarin. Compared with warfarin, edoxaban significantly reduced the incidence of cardiovascular death (CVD), major bleeding, and non-major bleeding (RR: 0.86, 95% CI: 0.80-0.93, I2 : 0.0%; RR: 0.65, 95% CI: 0.59-0.71, I2 : 75.6%; and RR: 0.80, 95% CI: 0.77-0.84, I2 : 79.3%, respectively). Edoxaban did not increase the incidence of stroke, systemic embolic events, myocardial infarction, and adverse events compared with warfarin (RR: 1.00, 95% CI: 0.90-1.11, I2 : 42.8%; RR: 1.00, 95% CI: 0.67-1.49, I2 : 0.0%; RR: 1.08, 95% CI: 0.93-1.27, I2 : 0.0%; RR: 1.00, 95% CI: 0.91-1.10, I2: 46.4%, respectively). This meta-analysis indicated that compared with warfarin, edoxaban can significantly reduce the incidence of CVD and major and non-major bleeding. The anticoagulant effect and safety of edoxaban may be better than those of warfarin.

Topics: Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Humans; Pyridines; Stroke; Thiazoles; Treatment Outcome; Warfarin

Non-vitamin K antagonist oral anticoagulants (NOACs) have been widely used for stroke prevention in atrial fibrillation (AF) and the treatment and prevention of venous thromboembolism. There is an issue with safety, especially in clinically relevant bleeding. We performed a network meta-analysis to evaluate the risk of major gastrointestinal (GI) bleeding associated with NOACs.. Interventions were warfarin, enoxaparin, apixaban, dabigatran, edoxaban, and rivaroxaban. The primary outcome was the incidence of major GI bleeding. A subgroup analysis was performed according to the following indications: AF, deep venous thrombosis/pulmonary embolism, and postsurgical prophylaxis.. A total of 29 randomized controlled trials (RCTs) and 4 large observation population studies were included. Compared with warfarin, apixaban showed a decreased the risk of major GI bleeding (relative risk [RR] 0.54, 95% confidence interval [CI] 0.25-0.76), and rivaroxaban tended to increase this risk (RR 1.40, 95% CI 1.06-1.85). Dabigatran (RR 1.25, 95% CI 0.98-1.60), edoxaban (RR 1.07, 95% CI 0.69-1.65), and enoxaparin (RR 1.24, 95% CI 0.63-2.43) did not significantly increase the risk of GI bleeding than did warfarin. In the subgroup analysis, according to indications, apixaban showed a decreased risk of major GI bleeding (RR 0.50, 95% CI 0.34-0.74) than did warfarin in AF studies. Dabigatran (RR 2.36, 95% CI 1.55-3.60, and rivaroxaban (RR 1.75, 95% CI 1.10-6.41) increased the risk of major GI bleeding than did apixaban. An analysis of studies on venous thromboembolism or pulmonary embolism showed that no individual NOAC or enoxaparin was associated with an increased risk of major GI bleeding compared to warfarin.. Individual NOACs had varying profiles of GI bleeding risk. Results of analyses including only RCTs and those including both RCTs and population studies showed similar trends, but also showed several differences.

Topics: Administration, Oral; Adult; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Enoxaparin; Female; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Network Meta-Analysis; Observational Studies as Topic; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Risk Factors; Rivaroxaban; Stroke; Thiazoles; Venous Thromboembolism; Warfarin

Major bleeding (especially intracranial hemorrhage) is the most feared adverse event observed in patients with atrial fibrillation (AF) receiving oral anticoagulation. Clinical risk factor-based scores have modest ability to predict major or clinically relevant bleeds, and blood biomarkers are increasingly implemented to improve bleeding prognostication in patients with AF on life‑long anticoagulation. To improve the safety of anticoagulation in the era of non-vitamin K antagonist oral anticoagulants (NOACs, or direct oral anticoagulants [DOACs], including dabigatran, rivaroxaban, apixaban, and edoxaban), specific demographic, clinical, and laboratory variables should be considered. The current review summarizes practical challenges in the management of oral anticoagulation with emphasis on the risk assessment tools, elderly or underweight patients, cancer patients, impact of chronic kidney disease, liver cirrhosis, and thrombocytopenia in the context of bleeding risk in patients with AF.

Topics: Anticoagulants; Atrial Fibrillation; Dabigatran; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles

Warfarin care bundles (e.g. genotype-guided warfarin dosing, patient's self-testing [PST] or patient's self-management [PSM] and left atrial appendage closure) are based on the concept of combining several interventions to improve anticoagulation care. NOACs are also introduced for stroke prevention in atrial fibrillation (SPAF). However, these interventions have not been compared in head-to-head trials yet. We did a network meta-analysis based on a systematic review of randomized controlled trials comparing anticoagulant interventions for SPAF. Studies comparing these interventions in adults, whether administered alone or as care bundles were included in the analyses. The primary efficacy outcome was stroke and the primary safety outcome was major bleeding. Thirty-seven studies, involving 100,142 patients were assessed. Compared to usual care, PSM significantly reduced the risk of stroke (risk ratio [RR] 0.24, 95% CI 0.08-0.68). For major bleeding, edoxaban 60 mg (0.80, 0.71-0.90), edoxaban 30 mg (0.48, 0.42-0.56), and dabigatran 110 mg (0.81, 0.71-0.94) significantly reduced the risk of major bleeding compared with usual warfarin care. Cluster rank plot incorporating stroke and major bleeding outcomes indicates that some warfarin care bundles perform as well as NOACs. Both interventions are therefore viable options to be considered for SPAF. Additional studies including head-to-head trials and cost-effectiveness evaluation are still warranted.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Hemorrhage; Humans; Male; Middle Aged; Patient Care Bundles; Pyridines; Randomized Controlled Trials as Topic; Stroke; Thiazoles; Treatment Outcome; Warfarin

Patients with chronic kidney disease (CKD) have a high prevalence of atrial fibrillation (AF). Stroke in patients with CKD and AF is frequent, and is usually more severe than in the absence of CKD. Current European Society of Cardiology guidelines recommend oral anticoagulant therapy in order to reduce thromboembolic risk in AF patients in general, and also in the presence of CKD, excluding however stage 4 and dialysis (stage 5) patients. Warfarin and other vitamin K antagonists are still the most frequently used drugs in these settings, despite the high bleeding risk. In the United States, the non-vitamin K antagonist oral anticoagulants, especially apixaban, are here used off-label, despite the absence of strong evidences of efficacy and safety. Several clinical trials are ongoing, and further evidence is needed before non-vitamin K antagonists can be recommended in these patients.

Topics: Administration, Oral; Age Factors; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Diabetes Complications; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Hypertension; Male; Middle Aged; Off-Label Use; Prevalence; Pyrazoles; Pyridines; Pyridones; Renal Insufficiency, Chronic; Risk Factors; Rivaroxaban; Sex Factors; Sleep Apnea, Obstructive; Stroke; Thiazoles; Thromboembolism

This meta-analysis aimed to evaluate the efficacy and safety of non-vitamin K antagonist oral anticoagulants (NOACs) versus vitamin K antagonists (VKAs) in secondary stroke prevention in atrial fibrillation (AF) patients.. PubMed and Embase electronic databases were systematically searched from January 2009 to July 2019 for relevant randomized clinical trials and observational studies. A random-effects model was applied in the pooled analysis.. A total of 14 studies (4 randomized clinical trials and 10 observational studies) were included. Based on the randomized clinical trials, compared with VKA use, the use of NOACs was associated with decreased risk of stroke and systemic embolism, major bleeding, and intracranial bleeding. Based on the observational studies, compared with VKAs, the subgroup analysis showed that dabigatran and rivaroxaban were associated with a reduced risk of stroke or systemic embolism, whereas dabigatran and apixaban were associated with a decreased risk of major bleeding.. Based on current data, the use of NOACs is at least non-inferior to the use of VKAs in AF patients for secondary stroke prevention irrespective of NOAC type.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Factor Xa Inhibitors; Humans; Intracranial Hemorrhages; Observational Studies as Topic; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Risk Factors; Rivaroxaban; Secondary Prevention; Stroke; Thiazoles; Treatment Outcome; Vitamin K; Warfarin

Ischaemic stroke and systemic embolism are the major potentially preventable complications of atrial fibrillation (AF) leading to severe morbidity and mortality. Anticoagulation using vitamin K antagonists (VKA) or non-vitamin K oral anticoagulants (NOACs) is mandatory for stroke prevention in AF. Following approval of the four NOACs dabigatran, rivaroxaban, apixaban, and edoxaban, the use of VKA is declining steadily. Increasing age with thresholds of 65 and 75 years is a strong risk factor when determining annual stroke risk in AF patients. Current recommendations such as the "2016 Guidelines for the management of atrial fibrillation" of the European Society of Cardiology and the "2019 AHA/ACC/HRS Focused Update" by the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society strengthen the importance of anticoagulation and detection of bleeding risks, of which older age is an important one. While patients aged ≥ 75 years are usually underrepresented in randomised clinical trials, they represent almost 40% of the trial populations in the large NOAC approval studies. Therefore, a sufficient amount of data is available to assess the efficacy and safety for this patient cohort in that specific indication. In this article, the evidence for stroke prevention in AF using either VKA or NOACs is summarised with a special focus on efficacy compared to bleeding risk in patients aged ≥ 75 years. Specifically, we used a model of increased weighing of intracranial bleeding to illustrate the potential benefit of NOACs over VKA in the elderly population. In brief, there are at least two tested strategies with apixaban and edoxaban which even confer an additional clinical net benefit compared with VKA. Furthermore, elderly subgroups of trials for combined antithrombotic treatment following percutaneous coronary interventions in anticoagulated patients are analysed.

Topics: Administration, Oral; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Factor Xa Inhibitors; Female; Humans; Intracranial Hemorrhages; Male; Pyrazoles; Pyridines; Pyridones; Risk Factors; Rivaroxaban; Stroke; Thiazoles; Treatment Outcome; Vitamin K; Warfarin

Given the huge burden of atrial fibrillation (AF) and AF-related stroke in Asia, stroke prevention represents an urgent issue in this region. We herein performed a network meta-analysis to examine the role of non-vitamin K antagonist oral anticoagulants (NOACs) in Asian patients with AF.. A systematic search of the publications was conducted in PubMed and Embase databases for eligible studies until July 2019. The odds ratios (ORs) and 95% confidence intervals (CIs) were regarded as the effect estimates. The surface under the cumulative ranking area (SUCRA) for the ranking probabilities was calculated.. A total of 17 studies were included. For comparisons of NOACs vs warfarin, dabigatran (OR = 0.77, 95% CI 0.68-0.86), rivaroxaban (OR = 0.72, 95% CI 0.65-0.81), apixaban (OR = 0.56, 95% CI 0.49-0.65), but not edoxaban reduced the risk of stroke or systemic embolism, wheres dabigatran (OR = 0.56, 95% CI 0.41-0.76), rivaroxaban (OR = 0.66, 95% CI 0.50-0.86), apixaban (OR = 0.49, 95% CI 0.36-0.66), and edoxaban (OR = 0.34, 95% CI 0.24-0.49) decreased the risk of major bleeding. In reducing the risk of stroke or systemic embolism, apixaban and rivaroxaban ranked the best and second best (SUCRA 0.2% and 31.4%, respectively), followed by dabigatran (50.2%), edoxaban (75.2%), and warfarin (93.0%). In reducing the risk of major bleeding, edoxaban, and apixaban ranked the best and second best (1.5% and 30.8%, respectively), followed by dabigatran (48.4%), rivaroxaban (69.2%), and warfarin (100%).. NOACs were at least as effective as warfarin, but more safer in Asians with AF. Apixaban was superior to other NOACs for reducing stroke or systemic embolism, while edoxaban showed a better safety profile than other NOACs.

Topics: Administration, Oral; Aged; Anticoagulants; Antithrombins; Asia; Asian People; Atrial Fibrillation; Cost of Illness; Dabigatran; Embolism; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Network Meta-Analysis; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Safety; Stroke; Thiazoles; Warfarin

This review analyzes results of a large prospective, randomized, double-blind, placebo-controlled clinical study ENGAGE AF-TIMI 48 that compared efficacy and safety of warfarin, a vitamin K antagonist, and edoxaban, an oral inhibitor of activated coagulation factor X. The review addresses important practical aspects of using edoxaban in patients with nonvalvular atrial fibrillation.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Double-Blind Method; Factor Xa Inhibitors; Humans; Prospective Studies; Pyridines; Randomized Controlled Trials as Topic; Stroke; Thiazoles; Treatment Outcome; Warfarin

Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) have several advantages over VKAs that render them an attractive option for adults with congenital heart disease (CHD). Efficacy and safety data specific to the adult CHD population are emerging. Herein, we synthesize the growing literature regarding NOACs in adults with CHD and attempt to identify subgroups for which it appears reasonable to extrapolate data from populations without CHD. Small observational studies suggest that NOACs are safe and effective in selected adults with CHD. NOACs are contraindicated in patients with a mechanical valve, in those with mitral or tricuspid valve stenosis with enlarged and diseased atria, with or without a mitral or tricuspid bioprosthesis, and after recent cardiac surgery (< 3 months). There is currently insufficient evidence to recommend NOACs in patients with a Fontan circulation or cyanotic CHD. Growing literature supports the use of NOACs in patients without CHD who have various forms of valvular heart disease. Therefore, when an indication for oral anticoagulation is established, it appears reasonable to consider a NOAC instead of a VKA in adults with CHD lesions analogous to isolated mitral regurgitation, tricuspid regurgitation, or aortic regurgitation or stenosis. The NOAC agent selected and the prescribed dose should be tailored according to bleeding risk, body weight, renal function, and comedications, especially antiepileptic drugs. The decision to initiate a NOAC should be shared between the patient and care provider. Large-scale research studies are required to further assess safety and efficacy in selected patient subgroups.

Topics: Administration, Oral; Adult; Age Factors; Anticoagulants; Antithrombins; Atrial Fibrillation; Blood Coagulation; Dabigatran; Female; Heart Defects, Congenital; Heart Valve Diseases; Humans; Male; Prognosis; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Severity of Illness Index; Sex Factors; Stroke; Survival Analysis; Thiazoles; Vitamin K

There is a lack of clear benefit and a potential risk of bleeding with direct oral anticoagulant (DOAC) use in chronic kidney disease (CKD) and dialysis patients with atrial fibrillation. The objective of this study was to evaluate how treatment with DOACs affects stroke and bleeding outcomes compared with warfarin or aspirin.. We conducted a systematic review of randomized controlled trials, cohort studies and case series, and searched electronic databases from 1946 to 2017. Studies evaluating stroke and bleeding outcomes with DOAC use in CKD and dialysis patients were included.. From 8008 studies, 10 met the inclusion criteria. For moderate CKD patients (estimated glomerular filtration rate  <60 mL/min/1.73 m2), there was no difference in stroke outcomes between dabigatran 110 mg [hazard ratio (HR) 0.78, 95% confidence interval (95% CI) 0.51-1.21], rivaroxaban (HR 0.82-0.84, 95% CI 0.25-2.69) and edoxaban (HR 0.87, 95% CI 0.65-1.18) versus warfarin. Dabigatran (150 mg twice daily) and apixaban reduced risk of stroke or systemic embolism significantly more than warfarin for moderate CKD patients (HR 0.55, 95% CI 0.34-0.89 and HR 0.61, 95% CI 0.39-0.94, respectively). Edoxaban and apixaban were associated with reduced major bleeding events (HR 0.50-0.76) compared with warfarin. Rivaroxaban and dabigatran 110 mg and 150 mg showed no significant difference in major bleeding versus warfarin. In hemodialysis (HD) patients, there was no difference in stroke outcomes between apixaban, dabigatran [relative risk (RR) 1.71, 95% CI 0.97-2.99] or rivaroxaban (RR 1.8, 95% CI 0.89-3.64) versus warfarin. In HD patients, rivaroxaban and dabigatran were associated with an increased major bleeding risk (RR 1.45-1.76), whereas there was no major bleeding difference with apixaban compared to warfarin.. The heterogeneity of major bleeding and stroke definitions of the 10 included studies.. Clinicians should continue to weigh the risk of stroke versus bleeding before prescribing DOACs in the CKD and dialysis population.

Topics: Administration, Oral; Anticoagulants; Aspirin; Atrial Fibrillation; Dabigatran; Embolism; Glomerular Filtration Rate; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Renal Dialysis; Renal Insufficiency, Chronic; Risk Factors; Rivaroxaban; Stroke; Thiazoles; Treatment Outcome; Warfarin

Patients with atrial fibrillation and concomitant coronary artery disease (CAD) are at higher risk for myocardial infarction or cardiovascular death, often require antiplatelet therapy and are therefore exposed to an increased risk of bleeding. This meta-analysis aimed to compare the efficacy and safety profile of non-vitamin K antagonist oral anticoagulants (NOACs) with warfarin in patients with atrial fibrillation and concomitant CAD.. We performed a trial-level meta-analysis of CAD subgroups from four trials of NOAC versus warfarin in patients with atrial fibrillation, comparing the primary trial endpoints (efficacy: stroke or systemic embolic event; safety: International Society on Thrombosis and Haemostasis major bleeding) in patients with versus those without CAD, and used interaction testing to assess for treatment effect modification.. In total, 58,606 patients with established CAD were included in this meta-analysis. NOACs reduced the risk of stroke/systemic embolic event irrespective of presence of CAD (CAD: 0.76 (0.56-1.04); no CAD: hazard ratio 0.77 (0.56-1.06);. The present meta-analysis of four trials supports that NOACs are safe and at least as effective as warfarin in patients with atrial fibrillation and established CAD.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Case-Control Studies; Clinical Trials, Phase III as Topic; Coronary Artery Disease; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Mortality; Myocardial Infarction; Pyridines; Randomized Controlled Trials as Topic; Safety; Stroke; Thiazoles; Treatment Outcome; Warfarin

Four non-vitamin K oral anticoagulants (NOACs) have been evaluated in clinical trials for the prevention of stroke in patients with atrial fibrillation (AF). Although each of the NOACs have been shown to be at least non-inferior to warfarin for efficacy and safety outcomes, controversy remains over the relative safety of each NOAC inpatient subgroups. This narrative review provides an overview of phase III data on NOAC trials for the prevention of stroke in AF, with a focus on reporting the safety of each agent in key patient subgroups based on age, gender, accumulated risk factors, and primary or secondary prevention of stroke.. A comprehensive literature search was completed and, where data permit, analyses of phase III trials of the NOACs are presented for each patient subgroup.. Analyses of key safety outcomes from NOAC trials were completed using primary trial data, including major bleeding and all-cause mortality. The safety of NOACs was generally consistent and favourable compared with warfarin according to patient age, gender, previous history of stroke, and the presence of risk factors for stroke.. The safety of the NOACs compared with warfarin was generally favourable across different patient subgroups, including those perceived to be at "high risk" for adverse outcomes. However, certain NOACs may be preferable to warfarin in some subgroups, based on indirect analyses.

Topics: Administration, Oral; Age Factors; Anticoagulants; Atrial Fibrillation; Clinical Trials, Phase III as Topic; Dabigatran; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Risk Factors; Rivaroxaban; Stroke; Thiazoles; Warfarin

Non-vitamin K antagonist oral anticoagulants (NOACs) require dose reductions according to patient or clinical factors for patients with atrial fibrillation (AF). In this meta-analysis, we aimed to assess outcomes with reduced-dose NOACs when given as pre-specified in pivotal trials.. Aggregated data abstracted from Phase III trials comparing NOACs with warfarin in patients with AF were assessed by treatment using risk ratios (RRs) and 95% confidence intervals (CIs) stratified by patient eligibility for NOAC dose reduction. Irrespective of treatments, annualized rates of stroke or systemic embolism and major bleeding were higher in patients eligible for reduced-dose NOACs than in those eligible for full-dose NOACs (2.70% vs. 1.60% and 4.35% vs. 2.87%, respectively). Effects of reduced-dose NOACs compared with warfarin in patients eligible for reduced-dose NOACs on stroke or systemic embolism [RR 0.84 (95% CI 0.69-1.03)] and on major bleeding [RR 0.70 (95% CI 0.50-0.97)] were consistent with those of full-dose NOACs relative to warfarin in those eligible for full-dose NOACs [RR 0.86 (95% CI 0.77-0.96) for stroke or systemic embolism and RR 0.87 (95% CI 0.70-1.08) for major bleeding; interaction P, 0.89 and 0.26, respectively]. In addition, NOACs were associated with reduced risks of haemorrhagic stroke, intracranial haemorrhage, fatal bleeding, and death regardless of patient eligibility for NOAC dose reduction (interaction P > 0.05 for each).. Patients eligible for reduced-dose NOACs were at elevated risk of thromboembolic and haemorrhagic complications when treated with anticoagulants. NOACs, when appropriately dose-adjusted, had an improved benefit-harm profile compared with warfarin. Our findings highlight the importance of prescribing reduced-dose NOACs for indicated patient populations.

Topics: Anticoagulants; Atrial Fibrillation; Dose-Response Relationship, Drug; Embolism; Factor Xa Inhibitors; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Intracranial Hemorrhages; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiazoles; Warfarin

Non-vitamin K antagonist oral anticoagulants (NOACs) include dabigatran, which inhibits thrombin, and apixaban, betrixaban, edoxaban and rivaroxaban, which inhibit factor Xa. In large clinical trials comparing the NOACs with the vitamin K antagonist (VKA) warfarin, dabigatran, apixaban, rivaroxaban and edoxaban were at least as effective for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism, but were associated with less intracranial bleeding. In addition, the NOACs are more convenient to administer than VKAs because they can be given in fixed doses without routine coagulation monitoring. Consequently, the NOACs are now replacing VKAs for these indications, and their use is increasing. Although, as a class, the NOACs have a favourable benefit-risk profile compared with VKAs, choosing among them is complicated because they have not been compared in head-to-head trials. Therefore, selection depends on the results of the individual trials, renal function, the potential for drug-drug interactions and preference for once- or twice-daily dosing. In addition, several 'special situations' were not adequately studied in the dedicated clinical trials. For these situations, knowledge of the unique pharmacological features of the various NOACs and judicious cross-trial comparison can help inform prescription choices. The purpose of this position article is therefore to help clinicians choose the right anticoagulant for the right patient at the right dose by reviewing a variety of special situations not widely studied in clinical trials.

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Anticoagulants; Arginine; Atrial Fibrillation; Benzamides; Biomarkers; Blood Coagulation; Clinical Trials as Topic; Dabigatran; Drug Administration Schedule; Factor Xa; Heart Diseases; Humans; Piperazines; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Risk; Rivaroxaban; Stroke; Thiazoles; Thrombin; Venous Thromboembolism; Vitamin K; Warfarin

Edoxaban is the last direct oral anticoagulant marketed for the prevention of stroke among patients with nonvalvular atrial fibrillation (AF). Areas covered: ENGAGE AF-TIMI 48 was the pivotal clinical trial that led to the approval of edoxaban 60 mg once daily. After the publication of this study, a great number of substudies and post hoc analyses have been published, together with some observational studies. The aim of this review was to update the current evidence about the use of edoxaban in AF patients. Expert opinion: In the ENGAGE AF-TIMI 48 trial, edoxaban 60 mg was noninferior to warfarin for the prevention of stroke or systemic embolism, but significantly reduced the risk of bleeding, major adverse cardiac events and death from cardiovascular causes. The relative efficacy and safety of edoxaban 60 mg compared with warfarin were independent of different clinical conditions, such as prior stroke, age, risk of falls, renal function, hepatic disease, ischemic heart disease, heart failure, valvular heart disease, or cancer. Data about the effectiveness and safety of edoxaban in real-life patients are scarce, but consistent with those of the pivotal clinical trial. Edoxaban seems a cost-effective alternative to warfarin among AF patients with moderate to high thromboembolic risk.

Topics: Anticoagulants; Atrial Fibrillation; Clinical Trials as Topic; Cost-Benefit Analysis; Factor Xa Inhibitors; Hemorrhage; Humans; Pyridines; Stroke; Thiazoles; Thromboembolism; Warfarin

Background Several studies have investigated the effect of non-vitamin K antagonist oral anticoagulants (NOACs) in atrial fibrillation (AF) patients with cancer, but the results remain controversial. Therefore, we conducted a meta-analysis to compare the efficacy and safety of NOACs versus warfarin in this population. Methods and Results We systematically searched the PubMed and Embase databases until February 16, 2019 for studies comparing the effect of NOACs with warfarin in AF patients with cancer. Risk ratios (RRs) with 95% CIs were extracted and pooled by a random-effects model. Five studies involving 8908 NOACs and 12 440 warfarin users were included. There were no significant associations between cancer status and risks of stroke or systemic embolism, major bleeding, or death in AF patients. Compared with warfarin, NOACs were associated with decreased risks of stroke or systemic embolism (RR, 0.52; 95% CI, 0.28-0.99), venous thromboembolism (RR, 0.37, 95% CI, 0.22-0.63), and intracranial or gastrointestinal bleeding (RR, 0.65; 95% CI, 0.42-0.98) and with borderline significant reductions in ischemic stroke (RR, 0.63; 95% CI, 0.40-1.00) and major bleeding (RR, 0.73; 95% CI, 0.53-1.00). In addition, risks of efficacy and safety outcomes of NOACs versus warfarin were similar between AF patients with and without cancer. Conclusions In patients with AF and cancer, compared with warfarin, NOACs had lower or similar rates of thromboembolic and bleeding events and posed a reduced risk of venous thromboembolism.

Topics: Anticoagulants; Atrial Fibrillation; Dabigatran; Embolism; Factor Xa Inhibitors; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Intracranial Hemorrhages; Neoplasms; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Venous Thromboembolism; Warfarin

Vitamin K antagonists were the only choice for chronic oral anticoagulation for more than half a century. Over the past few years, direct oral anticoagulants have emerged, including one direct thrombin inhibitor (dabigatran etexilate) and three factor Xa inhibitors (apixaban, edoxaban and rivaroxaban). In randomised controlled trials comparing direct oral anticoagulants with traditional vitamin K antagonists, the direct oral anticoagulants all showed a favourable benefit-risk balance in their safety and efficacy profile, in prevention of thromboembolic events in patients with atrial fibrillation and in the prevention and treatment of venous thromboembolism and acute coronary syndrome. In 2008, dabigatran was the first direct oral anticoagulant approved by the European Medicine Agency. Subsequently, rivaroxaban, apixaban and edoxaban were also authorised. This article reviews the evidence related to the use of these drugs.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Postoperative Complications; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Secondary Prevention; Stroke; Thiazoles; Venous Thromboembolism; Withholding Treatment

Because atrial fibrillation (AF) is a major risk for thrombotic disease, many patients with AF are managed with anticoagulation for primary or secondary prevention of these events. The emergence of novel oral anticoagulants offers patients and providers options to consider beyond warfarin. Decision making should address safety, tolerability, efficacy, price, and simplicity of use; and decisions should be individualized for each patient.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Humans; Male; Middle Aged; Pyrazoles; Pyridines; Pyridones; Risk Factors; Rivaroxaban; Stroke; Thiazoles; Thrombosis

Atrial fibrillation (AF) occurs approximately in 3% of general population, with greater prevalence in elderly. Non-vitamin K-dependent oral anticoagulant agents (NOACs) according to the current European guidelines are recommended for patients with AF at high risk for stroke as a first-choice treatment. NOACs are not inferior to warfarin or some of them are better than warfarin in reducing the rate of ischemic stroke. Moreover, they significantly reduce the rate of intracranial hemorrhages, major bleedings, and mortality compared with warfarin. Nevertheless according to ESC guidelines, NOACs are not recommended in patients with creatinine clearance < 30 mL/min. Observational studies provide contradictive data. Only few new trials are ongoing. Therefore, it is not clear if NOACs should be in the future prescribed to patients with advanced CKD and those on dialysis. Moreover, the risk of stroke and bleeding is much higher in such population than in patients without end-stage renal disease (ESRD). The authors provide data on pros and cons of use of NOACs in ESRD patients with AF.

Topics: Anticoagulants; Atrial Fibrillation; Brain Ischemia; Dabigatran; Humans; Practice Guidelines as Topic; Pyrazoles; Pyridines; Pyridones; Renal Dialysis; Renal Insufficiency, Chronic; Rivaroxaban; Stroke; Thiazoles

The introduction of NOACs has put a focus on stroke prevention in atrial fibrillation (AF). The number of patients in Stockholm diagnosed with non-valvular AF increased from 41 008 in 2011 to 51 266 in 2017 and their treatment has been markedly improved. Between 2011 and 2017 total oral anticoagulant treatment increased from 51.6% (warfarin) to 77.3% (31% warfarin, 46.3% NOACs) and aspirin decreased from 31.6% to 7.2%. Treatment was especially improved among patients with CHA2DS2-VASc scores ≥2 and elderly high risk patients. We found an excellent persistence with OAC treatment (88% at 1 year and 83% at 2 years). A comparative effectiveness study showed that NOACs were at least as effective and safe as warfarin even among patients ≥80 years or with previous serious bleeds. After a gradual introduction of NOACs with many educational activities apixaban is now the first-line choice for stroke prevention in AF in Stockholm. Swedish guideline goals are fulfilled and outcomes are improved.

Topics: Aged, 80 and over; Antithrombins; Atrial Fibrillation; Dabigatran; Humans; Ischemic Attack, Transient; Observational Studies as Topic; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Rivaroxaban; Stroke; Sweden; Thiazoles; Warfarin

Edoxaban is the most recent available representative of the Non-Vitamin K antagonist oral anticoagulants (NOAC). The approval was based on the largest phase III trials of NOACs for stroke prevention in patients with non-valvular atrial fibrillation (AF, ENGAGE-AF), and for the treatment of venous thromboembolism (VTE, HOKUSAI-VTE). In both trials, edoxaban was associated with similar efficacy and a significant reduction in bleeding events with respect to the pre-defined primary safety endpoints, as compared to warfarin.Additionally, the once daily dosing of edoxaban, the clinically investigated strategy for dose-reduction based on clearly defined criteria and the favorable pharmacokinetic profile might further support the clinical applicability of the substance.In the light of recent data, this expert consensus document aims to summarize the latest clinical trial results while providing a concise overview of current guideline recommendations on the management of patients with non-valvular AF and VTE.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Humans; Pyridines; Stroke; Thiazoles; Venous Thromboembolism

The non-vitamin K antagonist oral anticoagulants (NOACs) apixaban, dabigatran, edoxaban, and rivaroxaban are administered in fixed doses without anticoagulant monitoring. Randomized trials show that unmonitored NOAC therapy is at least as effective as and safer than dose-adjusted warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. Subgroup analyses indicate that plasma drug levels or anticoagulant activity of the NOACs predict stroke and bleeding. This review examines the historical basis for anticoagulant monitoring, discusses methods to measure and interpret drug levels, and critically assesses the role of routine laboratory monitoring in the management of NOAC therapy.. The predictable anticoagulant response of NOACs has provided the pharmacological basis for their administration in fixed doses without routine coagulation monitoring. Although it is possible to accurately measure NOAC drug levels, within-patient variability complicates interpretation of these results. Furthermore, patient characteristics, such as age and renal function, confound the association between NOAC drug levels and clinical outcomes. Information is lacking on the optimal drug level in particular patient groups (eg, elderly, the renally impaired, and those with high bleeding risk), the appropriate dose adjustment to achieve expected levels, and whether routine laboratory monitoring and dose adjustment will improve clinical outcomes. A benefit of a management strategy that incorporates routine therapeutic drug monitoring and dose adjustment over current standard-of-care metrics without such monitoring remains unproven.. Robust evidence from patients with atrial fibrillation randomized to NOACs or warfarin demonstrates that unmonitored NOAC therapy is at least as effective and safe as monitored warfarin, with lower rates of intracranial hemorrhage and reduced mortality. Further research is required to determine whether routine laboratory monitoring might provide a net benefit for patients. Until such data are available, clinicians should continue to prescribe NOACs in fixed doses without routine monitoring.

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Chromatography, High Pressure Liquid; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Intracranial Hemorrhages; Partial Thromboplastin Time; Prothrombin Time; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Tandem Mass Spectrometry; Thiazoles; Thrombin Time; Warfarin

Atrial fibrillation (AF) represents the most common arrhythmia in patients with chronic kidney disease (CKD). As in the general population, in CKD patients AF is associated with an increased risk of thromboembolism and stroke. However, CKD patients, especially those on renal replacement therapy (RRT), also exhibit an increased risk of bleeding, especially from the gastrointestinal tract. Oral anticoagulation is the most effective form of thromboprophylaxis in patients with AF presenting increased risk of stroke. Limited evidence on efficacy, the increased risk of bleeding as well as some concern regarding the use of warfarin in CKD, has often resulted in the underuse of anticoagulation CKD patients. A large body of evidence suggests that non-vitamin K-dependent oral anticoagulant agents (NOACs) significantly reduce the risk of stroke, intracranial hemorrhage, and mortality, with lower to similar major bleeding rates compared with vitamin K antagonist such as warfarin in normal renal function subjects. Hence, they are currently recommended for patients with atrial fibrillation at risk for stroke. However, NOACs metabolism is largely dependent on the kidneys for elimination and little is known in patients with creatinine clearance <25ml/min who were excluded from all pivotal phase 3 NOACs trials. This review focuses on the current pharmacokinetic, observational, and prospective data on NOACs in patients with moderate to advanced chronic kidney disease (creatinine clearance 15-49ml/min) and those on dialysis.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Hemorrhage; Humans; Prospective Studies; Pyrazoles; Pyridines; Pyridones; Renal Insufficiency, Chronic; Rivaroxaban; Stroke; Thiazoles; Thromboembolism; Warfarin

Age appropriateness of anticoagulants for stroke prevention in atrial fibrillation is uncertain.. To review oral anticoagulants for the treatment of atrial fibrillation in older (age >65 years) people and to classify appropriate and inappropriate drugs based on efficacy, safety and tolerability using the Fit-fOR-The-Aged (FORTA) classification.. We performed a structured comprehensive review of controlled clinical trials and summaries of individual product characteristics to assess study and total patient numbers, quality of major outcome data and data of geriatric relevance. The resulting evidence was discussed in a round table with an interdisciplinary panel of ten European experts. Decisions on age appropriateness were made using a Delphi process.. For the eight drugs included, 380 citations were identified. The primary outcome results were reported in 32 clinical trials with explicit and relevant data on older people. Though over 24,000 patients aged >75/80 years were studied for warfarin, data on geriatric syndromes were rare (two studies reporting on frailty/falls/mental status) and missing for all other compounds. Apixaban was rated FORTA-A (highly beneficial). Other non-vitamin K antagonist oral anticoagulants (including low/high-intensity dabigatran and high-intensity edoxaban) and warfarin were assigned to FORTA-B (beneficial). Phenprocoumon, acenocoumarol and fluindione were rated FORTA-C (questionable), mainly reflecting the absence of data.. All non-vitamin K antagonist oral anticoagulants and warfarin were classified as beneficial or very beneficial in older persons (FORTA-A or -B), underlining the overall positive assessment of the risk/benefit ratio for these drugs. For other vitamin-K antagonists regionally used in Europe, the lack of evidence should challenge current practice.

Topics: Administration, Oral; Age Factors; Aged; Anticoagulants; Atrial Fibrillation; Consensus; Dabigatran; Delphi Technique; Europe; Evidence-Based Practice; Female; Humans; Long-Term Care; Middle Aged; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Stroke; Thiazoles; Warfarin

Renal impairment increases risk of stroke and systemic embolic events and bleeding in patients with atrial fibrillation. Direct oral anticoagulants (DOACs) have varied dependence on renal elimination, magnifying the importance of appropriate patient selection, dosing, and periodic kidney function monitoring. In randomized controlled trials of nonvalvular atrial fibrillation, DOACs were at least as effective and associated with less bleeding compared with warfarin. Each direct oral anticoagulant was associated with reduced risk of stroke and systemic embolic events and major bleeding compared with warfarin in nonvalvular atrial fibrillation patients with mild or moderate renal impairment. Renal function decrease appears less impacted by DOACs, which are associated with a better risk-benefit profile than warfarin in patients with decreasing renal function over time. Limited data address the risk-benefit profile of DOACs in patients with severe impairment or on dialysis.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Embolism; Factor Xa Inhibitors; Hemorrhage; Humans; Pharmaceutical Research; Pyrazoles; Pyridines; Pyridones; Renal Insufficiency; Risk Assessment; Rivaroxaban; Stroke; Therapeutic Equivalency; Thiazoles; Warfarin

Rivaroxaban is a direct oral anticoagulant (DOAC) approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, a common arrhythmia. In this review, we summarize the effectiveness of rivaroxaban versus warfarin and the DOACs dabigatran, apixaban and edoxaban. The primary focus is on primary evidence from clinical trials, indirect comparison studies and real-world studies. While there are gaps in the literature, the evidence thus far indicates that rivaroxaban is superior to warfarin and similar to dabigatran, apixaban and edoxaban for the prevention of stroke or systemic embolism in patients with nonvalvular atrial fibrillation, although rivaroxaban may be associated with an elevated bleeding risk compared with other DOACs.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Drug Administration Schedule; Epidemiologic Methods; Factor Xa Inhibitors; Female; Humans; Male; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Treatment Outcome; Warfarin

Four direct oral anticoagulants (DOACs) are available for the prevention of stroke in nonvalvular atrial fibrillation (NVAF): dabigatran (a direct thrombin inhibitor); and rivaroxaban, apixaban, and edoxaban (factor Xa inhibitors). This article summarizes the safety and efficacy of DOACs for the prevention of stroke in elderly NVAF patients.. PubMed was searched to identify published results of randomized, controlled trials evaluating DOACs for stroke prevention in elderly NVAF patients. Pharmacologic and dose recommendations were obtained from the package inserts.. DOACs are at least as effective as warfarin for stroke prevention in elderly patients with NVAF. Compared with warfarin, DOACs were associated with reduced risk of intracranial hemorrhage, while some DOACs demonstrated an increase in other bleeding events (e.g., gastrointestinal). The faster onset and offset of action and fewer food and drug interactions of DOACs may be an advantage over warfarin for some patients.. DOACs are an alternative to warfarin with overall equivalent safety and efficacy in elderly patients with NVAF, and may be preferable for some. Stroke risk must always be balanced against potential bleeding risk when determining an optimal anticoagulation treatment plan. Patients' needs and preferences will also impact this decision.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Warfarin

Atrial Fibrillation (AF) has a worldwide increasing incidence and prevalence, putting patients at risk for atrial thrombus formation and consecutive thromboembolic events. Morbidity and mortality have become a significant global public health care burden. Thus, there is increasing need for safe and effective medical prophylaxis of thromboembolic events. Edoxaban is the fourth approved non-vitamin K oral anticoagulant (NOAC) that has been introduced into the market for the prophylaxis of stroke or systemic embolism in non valvulär AF patients after dabigatran, rivaroxaban, and apixaban. The pivotal phase III clinical trial evaluating safety and efficacy of edoxaban included more than 21,000 patients. Areas covered: The aim of this expert opinion drug safety review is to introduce edoxaban as a compound, to discuss its development, and its pharmacologic properties. Furthermore, efficacy and safety data of edoxaban - with emphasis on a comparison to oral anticoagulation with warfarin and the other currently available NOACs - are discussed. Ongoing studies that further evaluate edoxaban in special patient populations and disease entities are summarized. Expert opinion: Concerning safety and efficacy, medical compliance, adherence and concomitant diseases like renal impairment are of utmost importance in daily clinical practice, why in the expert opinion part of this review emphasis is put on that issue.

Topics: Administration, Oral; Animals; Atrial Fibrillation; Factor Xa Inhibitors; Humans; Medication Adherence; Pyridines; Stroke; Thiazoles; Thromboembolism

Chronic kidney disease (CKD) is an independent risk factor for atrial fibrillation (AF), which is more prevalent among CKD patients than the general population. AF causes stroke or systemic embolism, leading to increased mortality. The conventional antithrombotic prophylaxis agent warfarin is often prescribed for the prevention of stroke, but risk of bleeding necessitates regular therapeutic monitoring. Recently developed direct oral anticoagulants (DOAC) are expected to be useful as alternatives to warfarin.. To assess the efficacy and safety of DOAC including apixaban, dabigatran, edoxaban, and rivaroxaban versus warfarin among AF patients with CKD.. We searched the Cochrane Kidney and Transplant Specialised Register (up to 1 August 2017) through contact with the Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov.. We included all randomised controlled trials (RCTs) which directly compared the efficacy and safety of direct oral anticoagulants (direct thrombin inhibitors or factor Xa inhibitors) with dose-adjusted warfarin for preventing stroke and systemic embolic events in non-valvular AF patients with CKD, defined as creatinine clearance (CrCl) or eGFR between 15 and 60 mL/min (CKD stage G3 and G4).. Two review authors independently selected studies, assessed quality, and extracted data. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for the association between anticoagulant therapy and all strokes and systemic embolic events as the primary efficacy outcome and major bleeding events as the primary safety outcome. Confidence in the evidence was assessing using GRADE.. Our review included 12,545 AF participants with CKD from five studies. All participants were randomised to either DOAC (apixaban, dabigatran, edoxaban, and rivaroxaban) or dose-adjusted warfarin. Four studies used a central, interactive, automated response system for allocation concealment while the other did not specify concealment methods. Four studies were blinded while the other was partially open-label. However, given that all studies involved blinded evaluation of outcome events, we considered the risk of bias to be low. We were unable to create funnel plots due to the small number of studies, thwarting assessment of publication bias. Study duration ranged from 1.8 to 2.8 years. The large majority of participants included in this study were CKD stage G3 (12,155), and a small number were stage G4 (390). Of 12,545 participants from five studies, a total of 321 cases (2.56%) of the primary efficacy outcome occurred per year. Further, of 12,521 participants from five studies, a total of 617 cases (4.93%) of the primary safety outcome occurred per year. DOAC appeared to probably reduce the incidence of stroke and systemic embolism events (5 studies, 12,545 participants: RR 0.81, 95% CI 0.65 to 1.00; moderate certainty evidence) and to slightly reduce the incidence of major bleeding events (5 studies, 12,521 participants: RR 0.79, 95% CI 0.59 to 1.04; low certainty evidence) in comparison with warfarin.. Our findings indicate that DOAC are as likely as warfarin to prevent all strokes and systemic embolic events without increasing risk of major bleeding events among AF patients with kidney impairment. These findings should encourage physicians to prescribe DOAC in AF patients with CKD without fear of bleeding. The major limitation is that the results of this study chiefly reflect CKD stage G3. Application of the results to CKD stage G4 patients requires additional investigation. Furthermore, we could not assess CKD stage G5 patients. Future reviews should assess participants at more advanced CKD stages. Additionally, we could not conduct detailed analyses of subgroups and sensitivity analyses due to lack of data.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Embolism; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Rivaroxaban; Stroke; Thiazoles; Warfarin

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.

Topics: Administration, Oral; Atrial Fibrillation; Factor Xa Inhibitors; Humans; Pyridines; Stroke; Thiazoles

The majority of patients with atrial fibrillation should receive oral anticoagulation to reduce the risk of stroke. The limitations of vitamin K antagonists have led to an underuse of anticoagulants in clinical practice which has been associated with a higher risk of stroke, hospitalizations and healthcare costs. Direct oral anticoagulants (DOACs) overcome some of the limitations of vitamin K antagonists and may therefore increase the use of oral anticoagulants in clinical practice. Since no head-to-head trials have been performed, only indirect comparisons can be made among them. In this review, the results of the Phase III randomized controlled trials with DOACs were analyzed, trying to determine whether one or more DOACs could be especially recommended according to different clinical conditions.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Clinical Trials, Phase III as Topic; Dabigatran; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiazoles

With the rising prevalence of nonvalvular atrial fibrillation (NVAF) in the general population, the development of new drugs for prevention of thromboembolic events is essential. Non-vitamin K antagonist oral anticoagulants (NOACs) have been shown to present a number of advantages over conventionally used agents, such as predictable pharmacokinetics and no requirement for continuous anticoagulant monitoring. The most recently approved NOAC for the NVAF indication is edoxaban. Several subgroup analyses from the edoxaban phase III ENGAGE AF-TIMI 48 trial have now been published, alongside meta-analysis data comparing the four currently approved NOACs. Consequently, an updated review of the literature is merited. Areas covered: A PubMed search using the terms 'edoxaban', 'non-vitamin K antagonist oral anticoagulant', 'ENGAGE AF-TIMI 48', and 'atrial fibrillation' was performed and results screened for the most relevant English language publications. The market position, pharmacological profile, clinical efficacy, safety and tolerability of edoxaban are presented and discussed. Expert commentary: Edoxaban has been shown to have an efficacy similar or superior to that of warfarin, with a potentially lower risk of major bleeding and predictable, dose-dependent pharmacology. In order to clarify its position within the NOAC market, head-to-head comparative studies are required.

Topics: Animals; Atrial Fibrillation; Dose-Response Relationship, Drug; Embolism; Factor Xa Inhibitors; Hemorrhage; Humans; Pyridines; Stroke; Thiazoles

Atrial fibrillation (AF) is an independent risk factor for stroke. It is most prevalent in the elderly and frequently coexists with heart failure (HF). The joint occurrence of AF and HF further worsens prognosis. The prevention of thromboembolism is crucial in the management of AF. In recent years, new oral anticoagulants (NOACs) have been licensed for the prevention of stroke and systemic embolism in patients with AF. Areas covered: This article reviews the key published studies on the pharmacology, clinical efficacy and safety of edoxaban, the latest NOAC to receive approval for the AF indication. This potent and selective inhibitor of factor Xa shows predictable pharmacokinetic and pharmacodynamic profiles. Its efficacy and safety have been demonstrated in the pivotal, phase III, warfarin-controlled ENGAGE AF-TIMI 48 trial in 21,105 AF patients. Expert opinion: NOACs will likely improve the management of AF, with or without HF. Edoxaban has a favorable pharmacokinetic profile that supports its use in special patient populations, including patients aged ≥75 years, with HF, renal impairment, poor adherence, and on polypharmacy. Proven strategies of edoxaban dose-reduction for optimal use in the presence of moderate renal impairment, and/or use of strong P-gp inhibitors are available.

Topics: Administration, Oral; Aged; Atrial Fibrillation; Factor Xa Inhibitors; Heart Failure; Humans; Pyridines; Risk Factors; Stroke; Thiazoles; Thromboembolism

Atrial fibrillation (AF) ranks the most prevailing type of cardiac rhythm disorder and AF patients are associated with a significantly increased risk of stroke compared to others. This study is designed to assess the relative efficacy of several clinical events prevention anticoagulants in patients with AF. Conventional pairwise meta-analysis was performed with fixed-effect model initially, then network meta-analysis was performed with random-effects model within results illustrated by cumulative odds ratios (ORs) and corresponding 95% credible interval (CrI). The rank probabilities of each treatment outcomes were summarized by the surface under the cumulative ranking curve (SUCRA). We conducted a systematic review and collected key clinical data from 37 studies with respect to 5 anticoagulant treatments for AF. Patients treated with rivaroxaban and apixaban are associated with a reduced risk of stroke compared to those treated with warfarin (OR 0.72, 95% CrI 0.53 to 0.88; OR 0.68, 95% CrI 0.48 to 0.91). Rivaroxaban (SUCRA = 0.712) appears to be the most preferable one with respect to vascular events, and both apixaban (SUCRA = 0.720) and rivaroxaban (SUCRA = 0.678) are preferable to others with respect to stroke. Dabigatran outperforms others with respect to the outcome of mortality (SUCRA = 0.695), hemorrhage events (SUCRA = 0.747), and myocardial infarction (SUCRA = 0.620). In conclusion, dabigatran has a noticeable and comprehensive advantage compared to others with respect to preventing several complications including hemorrhage events, myocardial infarction, and mortality. In addition, apixaban may be the best choice of preventing stroke, and rivaroxaban is more preferable to others with respect to preventing vascular events.

Topics: Anticoagulants; Atrial Fibrillation; Dabigatran; Hemorrhage; Humans; Mortality; Myocardial Infarction; Network Meta-Analysis; Odds Ratio; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Warfarin

The pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, safety, and place in therapy of edoxaban for prevention of stroke in patients with nonvalvular atrial fibrillation (AF) and treatment of venous thromboembolism (VTE) are reviewed.. Although warfarin has been an established therapy for stroke prevention in AF and VTE, the need for agents with less monitoring requirements, fewer food and drug interactions, and a lower risk of major bleeding led to the development of direct oral anticoagulants (DOACs). Current DOACs work by either directly blocking thrombin (dabigatran) or inhibiting factor Xa (apixaban, edoxaban, and rivaroxaban). Edoxaban is the newest DOAC and only the second Food and Drug Administration-approved anticoagulant for once-daily administration. Unlike apixaban and rivaroxaban, edoxaban does not interact with the cytochrome P-450 system. The results of the ENGAGE AF-TIMI 48 and Hokusai-VTE trials demonstrated edoxaban's noninferiority to warfarin. However, the adverse-effect profile of edoxaban may limit the drug's use in clinical practice; in clinical trials, patients with AF who had a creatinine clearance of ≥95 mL/min had a higher rate of strokes with the use of edoxaban versus warfarin.. A review of the literature showed that edoxaban, the most recently approved DOAC, is noninferior to warfarin for management of VTE (after parenteral anticoagulant therapy) and for stroke risk reduction in many patients with nonvalvular AF.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Drug Monitoring; Factor Xa Inhibitors; Hemorrhage; Humans; Pyridines; Stroke; Thiazoles; Venous Thromboembolism; Warfarin

Direct oral anticoagulants (DOACs) are increasingly used for prevention and treatment of venous thromboembolism and for prevention of stroke in patients with nonvalvular atrial fibrillation. In phase III clinical trials that included more than 100,000 patients, the DOACs were at least as effective as vitamin K antagonists (VKAs) and were associated with less serious bleeding, particularly less intracranial bleeding. Real-world evidence supports these outcomes. Despite this, some physicians and patients are concerned about serious bleeding or emergencies unless specific reversal agents for the DOACs are available. However, in clinical trials performed without reversal agents, the outcome of major bleeds was similar or better in patients receiving DOACs than in those taking VKAs. Because of their short half-lives, supportive measures are sufficient to manage most bleeds in patients receiving DOACs. Anticoagulant reversal should only be considered with life-threatening bleeds, with bleeds that fail to respond to usual measures and in patients requiring urgent surgery. Idarucizumab is licensed for dabigatran reversal and andexanet alfa is likely to be soon licensed for reversal of rivaroxaban, apixaban, and edoxaban. To ensure responsible use of these agents, every hospital needs a bleeding management algorithm that identifies patients eligible for reversal and outlines appropriate dosing regimens.

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Anticoagulants; Atrial Fibrillation; Clinical Trials, Phase III as Topic; Dabigatran; Factor Xa; Forecasting; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Stroke; Thiazoles; Venous Thromboembolism

Current evidence indicates that heart failure (HF) confers a hyper-coagulable state that is associated with adverse events including stroke, systemic embolism, and mortality. This may be due to the elevated levels of pro-thrombotic and pro-inflammatory cytokines that are seen in patients with acute and chronic HF. Left ventricular wall motion abnormalities in patients with systolic dysfunction predispose to local thrombosis due to blood stasis as does atrial fibrillation (AF) which leads to blood stasis in regions of the atria. The high risk of thromboemboli in HF patients with AF has resulted in the use anticoagulation therapy to prevent the occurrence of catastrophic events. There is evidence, however, that the pro-inflammatory, pro-thrombotic state that exists in HF puts patients who are in sinus rhythm at risk. The novel oral anticoagulants (NOACs) have been shown in RCT to have at least equivalent efficacy in reducing stroke as warfarin while exposing patients to a lower risk of bleeding. The fact that the NOACs don't require routine monitoring to assure that patients remain within the therapeutic range and have relatively simple dosing requirements and a safer risk profile makes them attractive substitutes to warfarin in HF patients with atrial fibrillation and other conditions (e.g. deep venous thrombosis). Post hoc analyses from a subset of HF patients from the RCTs in AF patients have demonstrated similar findings as were reported in the entire populations that were included in the trials. As a result, NOACS are commonly used now in HF patients with AF. For HF patients with reduced ejection fraction in sinus rhythm, the use of warfarin in randomized clinical trials (RCT) to reduce stroke has been disappointing and associated with increase bleeding risk when compared to aspirin. The advantages of the NOACs over warfarin, however, raise the question of whether they might improve outcomes in HF patients who are in sinus rhythm. The currently ongoing COMMANDER-HF trial has been designed to address this issue. In this chapter we review evidence of existence of a prothombotic state in HF, the pharmacodynamics and clinical trials of the NOACs and the outcomes from NOAC substudies in the HF subgroup. We also discuss the rationale for using anticoagulation in HF independent of arrhythmia burden.

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Heart Failure; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Venous Thromboembolism; Warfarin

The non-vitamin K antagonist oral anticoagulants (NOACs) are replacing warfarin for stroke prevention in many patients with nonvalvular atrial fibrillation. Edoxaban, an oral factor Xa inhibitor, is the newest entrant in this class. Results of the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation (ENGAGE AF) study demonstrate that edoxaban is noninferior to warfarin for prevention of stroke and systemic embolic events, and is associated with significantly less major bleeding, including intracranial bleeding, and reduced cardiovascular mortality. With a net clinical benefit over warfarin, edoxaban is well positioned as a choice among the NOACs, which include dabigatran, rivaroxaban, and apixaban. But how will clinicians choose amongst them? The purpose of this paper is to (a) place the ENGAGE AF trial results into context with results of the studies with the other NOACs, and (b) aid clinicians in selection of the right anticoagulant for the right atrial fibrillation patient.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Dabigatran; Embolism; Factor Xa Inhibitors; Female; Humans; Intracranial Hemorrhages; Male; Pyrazoles; Pyridines; Pyridones; Research Design; Rivaroxaban; Stroke; Thiazoles; Warfarin

The novel oral anticoagulants or direct oral anticoagulants (DOAC) are becoming more common in clinical practice for the prevention of stroke in non-valvular atrial fibrillation (NVAF). The availability of several agents with similar efficacy and safety for stroke prevention in NVAF patients offers more selection, but at the same time requires certain knowledge to make a good choice. This comparative analysis provides an appraisal of the respective clinical trials and highlights much of what remains unknown about four FDA-approved agents: dabigatran, apixaban, rivaroxaban, and edoxaban. It details how the DOACs compare to warfarin and to one another summarizes pharmacologic and pharmacodynamic properties, and drug interactions from the stand point of practical consequences of these findings. Common misconceptions and reservations are addressed. The practical application of this data is intended to help choosing the most appropriate agent for individual NVAF patient.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; beta-Alanine; Clinical Decision-Making; Dabigatran; Humans; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Stroke; Thiazoles; Warfarin

Benefits and/or harms (including costs) of non-vitamin K oral anticoagulants (NOACs) versus warfarin therapy need appreciation in relative and absolute terms.. Accordingly, we derived clinically relevant relative and absolute benefit/harm parameters for NOACs (apixaban, dabigatran, rivaroxaban, edoxaban) compared to warfarin from four clinical trials involving atrial fibrillation (AF) patients. For each trial, we tabulated patient numbers enduring four important outcomes and calculated unadjusted relative risk reduction (RRR) and number needed to treat (NNT)/year values (and 95% confidence intervals) for the NAOC compared to warfarin. These outcomes were as follows: stroke/systemic embolism (primary endpoint), hemorrhagic stroke, major bleeds, and death. We also addressed drug acquisition costs.. Each NOAC was noninferior to warfarin for primary-outcome prevention; RRRs were 12-33% and NNT/year values were 182-481, and all but one indicated statistically significant superiority. All the NOACs yielded statistically significant reductions in hemorrhagic stroke risk; RRRs were 42-74% and NNT/year values were 364-528. Major bleeding risk was comparable in both groups. Apixaban yielded a lower NNT/year for preventing death than for primary-outcome prevention. Compared to warfarin, NOAC acquisition costs were 70- to 140-fold greater.. For the primary outcome, the absolute benefits of NOACs were modest (NNT/year values being large). Reduced hemorrhagic stroke rates with NOACs could be due to superior embolic infarct prevention and fewer consequential hemorrhagic transformations. Among apixaban recipients, the absolute mortality benefit exceeded that for the primary outcome, indicating prevention of additional unrelated deaths. The substantially greater NOAC acquisition costs need viewing against probable greater safety and the avoidance of monitoring bleeding risks.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Humans; Male; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Rivaroxaban; Stroke; Thiazoles; Warfarin

Atrial fibrillation (AF) and the associated risk of stroke are emerging epidemics throughout the world. Suboptimal use of oral anticoagulants for stroke prevention has been widely reported from observational studies. In recent years, direct oral anticoagulants (DOACs) have been introduced for thromboprophylaxis. We conducted a systematic literature review to evaluate current practices of anticoagulation in AF, pharmacologic features and adoption patterns of DOACs, their impacts on proportion of eligible patients with AF who receive oral anticoagulants, persisting challenges and future prospects for optimal anticoagulation.. In conducting this review, we considered the results of relevant prospective and retrospective observational studies from real-world practice settings. PubMed (MEDLINE), Scopus (RIS), Google Scholar, EMBASE and Web of Science were used to source relevant literature. There were no date limitations, while language was limited to English. Selection was limited to articles from peer reviewed journals and related to our topic.. Most studies identified in this review indicated suboptimal use of anticoagulants is a persisting challenge despite the availability of DOACs. Underuse of oral anticoagulants is apparent particularly in patients with a high risk of stroke. DOAC adoption trends are quite variable, with slow integration into clinical practice reported in most countries; there has been limited impact to date on prescribing practice.. Available data from clinical practice suggest that suboptimal oral anticoagulant use in patients with AF and poor compliance with guidelines still remain commonplace despite transition to a new era of anticoagulation featuring DOACs.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Blood Coagulation Factors; Dabigatran; Dose-Response Relationship, Drug; Evidence-Based Medicine; Factor Xa Inhibitors; Humans; Medication Errors; Practice Guidelines as Topic; Practice Patterns, Physicians'; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Risk Factors; Rivaroxaban; Stroke; Thiazoles; Warfarin

Atrial fibrillation (AF) is associated with an increased risk of stroke. AF-related strokes cause greater disability and mortality than those in patients without AF, and are associated with a significant clinical and economic burden in Mexico. Antithrombotic therapy reduces stroke risk in patients with AF and is recommended for all patients except those classified as having a low stroke risk. However, its use is suboptimal all around the world; one study showed that only 4 % of Mexican patients with AF who presented with ischemic stroke were in the therapeutic range for anticoagulation. Vitamin K antagonists (VKAs) such as warfarin or acenocoumarin have long been the only oral anticoagulants for stroke prevention in AF. Although effective, VKAs have disadvantages, including the need for regular coagulation monitoring and dose adjustment. Interactions with numerous common medications and foods contribute to the risk of serious bleeding and thrombotic events in VKA-treated patients. Thus novel oral anticoagulants (NOACs), more properly called direct oral anticoagulants (DOACs), such as dabigatran etexilate, rivaroxaban, apixaban, and edoxaban (not available in Mexico), have been developed. These offer the convenience of fixed-dose treatment without the need for monitoring, and have few drug or food interactions. Pivotal phase III trials have demonstrated that these agents are at least as effective as warfarin in preventing stroke and are associated with a reduced risk of intracranial hemorrhage. With apixaban approved in Mexico in April 2013, clinicians now have the choice of three novel DOACs as alternatives to warfarin. However, it is yet to be established which of these agents should be the first choice, and treatment decisions are likely to depend on the individual patient's characteristics.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Drug Administration Schedule; Drugs, Investigational; Evidence-Based Medicine; Humans; Mexico; Practice Guidelines as Topic; Precision Medicine; Pyrazoles; Pyridines; Pyridones; Risk Factors; Rivaroxaban; Stroke; Thiazoles; Vitamin K

In recent years, small oral compounds that specifically block activated coagulation factor X (FXa) or thrombin (FIIa) have become alternatives to the anticoagulants that had been used for several decades. As of today, these direct oral anticoagulants (DOACs) include dabigatran etexilate (thrombin inhibitor) and apixaban, edoxaban and rivaroxaban (inhibitors of FXa). While there is no doubt that DOACs represent a major step forward in the management of patients with venous thromboembolic disease and atrial fibrillation, new challenges have arisen. They need to be addressed with the necessary pragmatism on the basis of evidence. Indeed, a better understanding of the management of these last-generation antithrombotics will favour safer use and increase confidence of the practitioner for the prescription of these drugs. The aim of this article is to present practical suggestions for the prescription and use of these drugs in everyday clinical practice, based on clinical experience and recently updated recommendations of the European Heart Rhythm Association and the American College of Chest Physicians among other scientific organisations. We address issues such as pharmacokinetics, dosing, side effects, limitations of use, drug interactions, switching from and to other anticoagulants, renal function, concomitant administration of antiplatelet agents and perioperative use. We also address the issue of monitoring and reversal, taking advantage of the most recent development in this latter area. Rather than being one additional set of recommendations, our narrative review aims at assisting the practicing physician in his or her daily handling of these novel anticoagulant compounds, based on frequently asked questions to the authors, a group of experienced specialists in the field who have, however, no commitment to issue guidelines.

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Factor Xa Inhibitors; Humans; Practice Guidelines as Topic; Pyrazoles; Pyridines; Pyridones; Recurrence; Rivaroxaban; Stroke; Thiazoles; Venous Thromboembolism

Oral anticoagulation is the therapeutic cornerstone in preventing thromboembolic risk in both atrial fibrillation (AF) and venous thromboembolism (VTE). After decades of the sole therapeutic oral anticoagulation option being warfarin, the introduction of non-vitamin K antagonist oral anticoagulants has heralded a new era. Edoxaban is the latest addition to these available for clinical use. Edoxaban was as effective and safer than warfarin in preventing thromboembolic risk in AF patients. Similarly, edoxaban effectiveness and safety was evident when treating VTE patients to prevent recurrent VTE or VTE-related death. Therefore, edoxaban represents a valuable alternative in treating thromboembolic risk for AF and VTE patients.

Topics: Administration, Oral; Animals; Anticoagulants; Antidotes; Atrial Fibrillation; Blood Coagulation; Coagulants; Hemorrhage; Humans; Pyridines; Recurrence; Risk Factors; Stroke; Thiazoles; Treatment Outcome; Venous Thromboembolism

Edoxaban is a once-daily oral inhibitor of factor Xa, currently indicated to reduce the risk of stroke or systemic embolism in nonvalvular atrial fibrillation patients and for the treatment and prevention of venous thromboembolism (EMA, FDA and Japan). The ENGAGE AF-TIMI 48 and the Hokusai-VTE trials demonstrated that edoxaban was at least as effective as warfarin for the prevention of stroke or systemic embolism in nonvalvular atrial fibrillation patients, as well as for the prevention and treatment of venous thromboembolism, but with a lesser risk of bleeding in both cases. In addition, it seems a cost-effective strategy for the management of this population. In this review, the implications of the most recent available evidence about edoxaban in clinical practice will be updated.

Topics: Atrial Fibrillation; Embolism; Factor Xa Inhibitors; Humans; Pyridines; Stroke; Thiazoles; Venous Thromboembolism

The most common cardiogenic cause of ischaemic stroke is atrial fibrillation which increases the probability of stroke five-fold and doubles case fatality. Based on international data the incidence of atrial fibrillation is approx. 2% however this rapidly increases with age. The necessity of using oral anticoagulants in the prevention of non-valvular atrial fibrillation related stroke is decided based on estimated stroke risk. The CHADS2 and the more predictive CHA2DS2-VASc scales are used for this purpose while the bleeding risk of patients treated with anticoagulant may be estimated by the HAS-BLED scoring scale. For decades oral anticoagulation meant using vitamin-K antagonists. Based on international data we can see that rate of anticoagulation is unacceptably low, furthermore most of the anticoagulated patients aren't within the therapeutic range of INR (INR: 2-3). A lot of disadvantages of vitamin-K antagonists are known (e.g. food-drug interaction, need for regular coagulation monitoring, increased risk of bleeding), therefore compounds with new therapeutic target have been developed. The novel oral anticoagulants (NOAC) can be divided in two major subgroups: direct thrombin inhibitors (dabigatran etexilate) and Xa-factor inhibitors (rivaroxaban, apixaban, edoxaban). These products are administered in fix doses, they less frequently interact with other medications or food, and regular coagulation monitoring is not needed when using these drugs. Moreover several studies have shown that they are at least as effective in the prevention of ischaemic stroke than the vitamin-K antagonists, with no more haemorrhagic complications.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Humans; Prevalence; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles

The goal of this study was to compare the safety and effectiveness of individual antiembolic interventions in nonvalvular atrial fibrillation (AF): novel oral anticoagulants (NOACs) (apixaban, dabigatran, edoxaban, and rivaroxaban); vitamin K antagonists (VKA); aspirin; and the Watchman device.. A network meta-analysis of randomized, clinical trials (RCTs) was performed. RCTs that included patients with prosthetic cardiac valves or mitral stenosis, mean or median follow-up <6 months, <200 participants, without published report in English language, and NOAC phase II studies were excluded. The placebo/control arm received either placebo or no treatment. The primary efficacy outcome was the combination of stroke (of any type) and systemic embolism. All-cause mortality served as a secondary efficacy outcome. The primary safety outcome was the combination of major extracranial bleeding and intracranial hemorrhage. A total of 21 RCTs (96 017 nonvalvular AF patients; median age, 72 years; 65% males; median follow-up, 1.7 years) were included. In comparison to placebo/control, use of aspirin (odds ratio [OR], 0.75 [95% CI, 0.60-0.95]), VKA (0.38 [0.29-0.49]), apixaban (0.31 [0.22-0.45]), dabigatran (0.29 [0.20-0.43]), edoxaban (0.38 [0.26-0.54]), rivaroxaban (0.27 [0.18-0.42]), and the Watchman device (0.36 [0.16-0.80]) significantly reduced the risk of any stroke or systemic embolism in nonvalvular AF patients, as well as all-cause mortality (aspirin: OR, 0.82 [0.68-0.99]; VKA: 0.69 [0.57-0.85]; apixaban: 0.62 [0.50-0.78]; dabigatran: 0.62 [0.50-0.78]; edoxaban: 0.62 [0.50-0.77]; rivaroxaban: 0.58 [0.44-0.77]; and the Watchman device: 0.47 [0.25-0.88]). Apixaban (0.89 [0.80-0.99]), dabigatran (0.90 [0.82-0.99]), and edoxaban (0.89 [0.82-0.96]) reduced risk of all-cause death as compared to VKA.. The entire spectrum of therapy to prevent thromboembolism in nonvalvular AF significantly reduced stroke/systemic embolism events and mortality.

Topics: Anticoagulants; Atrial Appendage; Atrial Fibrillation; Dabigatran; Hemorrhage; Humans; Intracranial Hemorrhages; Network Meta-Analysis; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Warfarin

Four non-vitamin K antagonist oral anticoagulants (dabigatran, rivaroxaban, apixaban, and edoxaban) have been approved in the United States for treatment of atrial fibrillation (AF) and venous thromboembolic disease. They have been as or more effective than the prior standards of care, with less fatal or intracranial bleeding, fewer drug and dietary interactions, and greater patient convenience. Nonetheless, the absence of the ability for clinicians to assess compliance or washout with a simple laboratory test (or to adjust dosing with a similar assessment) and the absence of an antidote to rapidly stop major hemorrhage or to enhance safety in the setting of emergent or urgent surgery/procedures have been limitations to greater non-vitamin K antagonist oral anticoagulant usage and better thromboembolic prevention. Accordingly, a Cardiac Research Safety Consortium "think tank" meeting was held in February 2015 to address these concerns. This manuscript reports on the discussions held and the conclusions reached at that meeting.

Topics: Antibodies, Monoclonal, Humanized; Antidotes; Antithrombins; Arginine; Atrial Fibrillation; Congresses as Topic; Dabigatran; Drug Monitoring; Factor Xa; Factor Xa Inhibitors; Humans; Partial Thromboplastin Time; Piperazines; Product Surveillance, Postmarketing; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Stroke; Thiazoles; Thrombin Time; Venous Thromboembolism

Nonvitamin K-dependent oral anticoagulant agents (NOACs) are currently recommended for patients with atrial fibrillation at risk for stroke. As a group, NOACs significantly reduce stroke, intracranial hemorrhage, and mortality, with lower to similar major bleeding rates compared with warfarin. All NOACs are dependent on the kidney for elimination, such that patients with creatinine clearance <25 ml/min were excluded from all the pivotal phase 3 NOAC trials. It therefore remains unclear how or if NOACs should be prescribed to patients with advanced chronic kidney disease and those on dialysis. The authors review the current pharmacokinetic, observational, and prospective data on NOACs in patients with advanced chronic kidney disease (creatinine clearance <30 ml/min) and those on dialysis. The authors frame the evidence in terms of risk versus benefit to bring greater clarity to NOAC-related major bleeding and efficacy at preventing stroke specifically in patients with creatinine clearance <30 ml/min.

Topics: Anticoagulants; Atrial Fibrillation; Creatinine; Dabigatran; Glomerular Filtration Rate; Hemorrhage; Humans; Kidney; Kidney Failure, Chronic; Pyrazoles; Pyridines; Pyridones; Renal Dialysis; Renal Insufficiency, Chronic; Rivaroxaban; Stroke; Thiazoles; Warfarin

Non-valvular atrial fibrillation (NVAF) is the most common cardiac source of emboli in cardioembolic stroke which occupies from 1/4 to 1/3 of acute brain infarction in Japan. Non-vitamin K antagonist oral anticoagulants (NOAC) have been used widely because they are easy to use, their effect in preventing ischemic stroke is higher than or as high as warfarin, their incidence of major hemorrhage is lower than or as low as warfarin, and their incidence of intracranial hemorrhage is much lower than warfarin. However, there seem several issues to address regarding NOAC treatment, such as reversal of anticoagulation, antidotes, monitoring of anticoagulation, rt-PA treatment for acute stroke patients treated with NOACs. In this review, current strategies and issues of anticoagulation for prevention of stroke in NVAF are discussed.

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Factor Xa Inhibitors; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thrombolytic Therapy; Warfarin

The new generation of target-specific oral anticoagulants is being prescribed for increasing numbers of patients at risk of stroke or venous thromboembolism (VTE). These drugs offer valuable benefits due to fast onset anticoagulation, a fixed anticoagulation effect (allowing administration of specified doses), and no requirement for routine monitoring. Edoxaban is a fast-acting oral anticoagulant, approved for use in the prevention of stroke in patients with nonvalvular atrial fibrillation (AF) and in the treatment of acute VTE. Like many of the new oral anticoagulants, it selectively inhibits factor Xa, in a concentration-dependent manner. Multiple Phase II clinical trials have shown edoxaban to be noninferior to vitamin K antagonists in the prevention of stroke and VTE, with a good safety profile. To date, the pivotal studies to endorse edoxaban's clinical use have been ENGAGE AF-TIMI and Hokusai-VTE, both of which have compared its efficacy to standard warfarin treatment. This paper aims at reviewing the use of edoxaban in the management of stroke and thromboembolic disease, highlighting the key study results that have led to its current license.

Topics: Administration, Oral; Atrial Fibrillation; Blood Coagulation; Factor Xa Inhibitors; Hemorrhage; Humans; Pyridines; Risk Factors; Stroke; Thiazoles; Treatment Outcome; Venous Thromboembolism

The risk of bleeding in the setting of anticoagulant therapy continues to be re-evaluated following the introduction of a new generation of direct oral anticoagulants (DOACs). Interruption of DOAC therapy and supportive care may be sufficient for the management of patients who present with mild or moderate bleeding, but in those with life-threatening bleeding, a specific reversal agent is desirable. We review the phase 3 clinical studies of dabigatran, rivaroxaban, apixaban, and edoxaban in patients with nonvalvular atrial fibrillation, in the context of bleeding risk and management.

Topics: Administration, Oral; Anticoagulants; Antidotes; Atrial Fibrillation; Clinical Trials, Phase III as Topic; Dabigatran; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Warfarin

This study investigated the efficacy and safety of novel oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) and heart failure (HF) by a meta-analysis.. AF is quite prevalent in patients with HF.. Four phase III clinical trials comparing NOACs to warfarin in patients with AF were included. Each patient was defined as affected by HF according to the criteria of the trial in which the patient was enrolled. Pre-specified outcomes were the composite of stroke/systemic embolism (SSE); major, intracranial, and any bleeding; and cardiovascular (CV) and all-cause death.. A total of 55,011 patients were enrolled, 26,384 (48%) with HF, and 28,627 (52%) without HF; 27,518 receiving NOACs and 27,493 receiving warfarin (median, 70 years of age; 36% females; follow-up: 1.5 to 2.8 years). Rates of SSE (relative risk [RR]: 0.98; 95% confidence interval [CI]: 0.90 to 1.07]; p = 0.68) and major bleeding (RR: 0.95; 95% CI: 0.88 to 1.03; p = 0.21) were comparable in patients with and without HF. HF patients had reduced rates of any (RR: 0.86; 95% CI: 0.81 to 0.91; p < 0.01) and intracranial (RR: 0.74 95% CI: 0.63 to 0.88; p < 0.01) bleeding but increased rates of all-cause (RR: 1.70 95% CI: 1.31 to 2.19; p < 0.01) and CV death (RR: 2.05 95% CI: 1.66 to 2.55; p < 0.01). NOACs, compared with warfarin significantly reduced SSE and major, intracranial, and any bleeding, regardless of the presence or absence of HF (p. Patients with AF and HF had increased mortality but reduced rates of intracranial and any bleeding compared with the no-HF patients, with no differences in rates of SSE and major bleeding. NOACs significantly reduced SSE, major bleeding, and intracranial hemorrhage in HF patients. No interactions in efficacy and safety of NOACs were observed between AF patients with and without HF.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Cardiovascular Diseases; Cause of Death; Dabigatran; Embolism; Factor Xa Inhibitors; Heart Failure; Hemorrhage; Humans; Intracranial Hemorrhages; Mortality; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Treatment Outcome; Warfarin

In studying the comparative effectiveness of novel oral anticoagulants (NOACs) in orthopedic surgery and in non-valvular atrial fibrillation, previous meta-analyses have found no proof of difference in head-to-head indirect comparisons between individual agents. However, the question of their therapeutic equivalence remains unanswered.. The objective of this analysis was to test the equivalence of three NOACs (dabigatran, rivaroxaban, apixaban) in orthopedic surgery and four NOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) in non-valvular atrial fibrillation.. Standard pairwise meta-analysis and network meta-analysis for indirect comparisons were combined with equivalence testing. The endpoint was venous thromboembolism in orthopedic surgery and a composite of stroke or systemic embolism in atrial fibrillation. Comparisons were expressed as risk difference (RD). Margins for equivalence testing were derived from the original trials.. Our results indicate that rivaroxaban and apixaban (but not dabigatran) are equivalent for thromboprophylaxis in orthopedic surgery. In atrial fibrillation, all the four NOACs we tested were found to meet the criterion of therapeutic equivalence. Some concern, however, is raised by some findings focused on adverse events of these agents, in which the equivalence was not proven in all analyses.. Regardless of clinical implications, our results can be the basis to develop local acquisition tenderings on NOACS. In Italy, a new law has been issued according to which equivalence analyses have become a mandatory prerequisite for local tenderings.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Blood Coagulation; Dabigatran; Humans; Morpholines; Orthopedic Procedures; Patient Safety; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Rivaroxaban; Stroke; Therapeutic Equivalency; Thiazoles; Thiophenes; Treatment Outcome; Venous Thromboembolism

As a class, the target-specific oral anticoagulants (TSOACs) are at least as effective as warfarin, often with superior safety for the prevention of stroke in patients with nonvalvular atrial fibrillation (AF) and the treatment of acute venous thromboembolism (VTE) and prevention of recurrent VTE. Currently, dabigatran, the direct thrombin inhibitor, along with rivaroxaban and apixaban, direct factor Xa inhibitors, has been approved in multiple countries for these indications. Edoxaban, which has received approval for the abovementioned indications in Japan, has demonstrated efficacy and safety comparable to or better than warfarin in Phase III clinical trials and is under further regulatory consideration. It is anticipated that the use of TSOACs will increase as practitioners and healthcare systems gain familiarity with these drugs and adopt their use into clinical practice. This review will provide a brief overview of the TSOAC Phase III clinical trials for prevention of stroke and systemic embolic events in patients with AF and the Phase III clinical trials for the prevention of recurrent VTE, discuss current treatment guidelines, address how TSOACs may help meet national safety goals, and provide clinical decision-making guidance regarding the use of TSOACs for hospitalists.

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Clinical Trials, Phase III as Topic; Dabigatran; Factor Xa Inhibitors; Hospitalists; Humans; International Normalized Ratio; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Venous Thrombosis; Warfarin

The target-specific oral anticoagulants are a class of agents that inhibit factor Xa or thrombin. They are effective and safe compared to warfarin for the prevention of stroke and systemic embolism in patients with atrial fibrillation and for the treatment of venous thromboembolism, and they are comparable to low-molecular-weight heparin for thromboprophylaxis after hip or knee arthroplasty. For other indications, however, such as the prevention of stroke in patients with mechanical heart valves, initial studies have been unfavorable for the newer agents, leaving warfarin the anticoagulant of choice. Further studies are needed before the target-specific anticoagulants can be recommended for patients with cancer-associated thrombosis or heparin-induced thrombocytopenia. Concerns also persist about difficulties with the laboratory assessment of anticoagulant effect and the lack of a specific reversal agent. For these reasons, we anticipate that the vitamin K antagonists will continue to be important anticoagulants for years to come.

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Venous Thromboembolism; Warfarin

The non-vitamin K antagonist oral anticoagulants (NOACs) are replacing warfarin for many indications. These agents include dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, and edoxaban, which inhibit factor Xa. All 4 agents are licensed in the United States for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism and rivaroxaban and apixaban are approved for thromboprophylaxis after elective hip or knee arthroplasty. The NOACs are at least as effective as warfarin, but are not only more convenient to administer because they can be given in fixed doses without routine coagulation monitoring but also are safer because they are associated with less intracranial bleeding. As part of a theme series on the NOACs, this article (1) compares the pharmacological profiles of the NOACs with that of warfarin, (2) identifies the doses of the NOACs for each approved indication, (3) provides an overview of the completed phase III trials with the NOACs, (4) briefly discusses the ongoing studies with the NOACs for new indications, (5) reviews the emerging real-world data with the NOACs, and (6) highlights the potential opportunities for the NOACs and identifies the remaining challenges.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dabigatran; Dose-Response Relationship, Drug; Drug Administration Schedule; Factor Xa Inhibitors; Female; Humans; Male; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Sensitivity and Specificity; Stroke; Thiazoles; Thiophenes; Thromboembolism; Warfarin

To evaluate the current literature and potential clinical role of edoxaban (Savaysa) for stroke prevention in nonvalvular atrial fibrillation (NVAF) and treatment of deep-vein thrombosis and pulmonary embolism.. A PubMed and Cochrane Central Register of Controlled trials search was conducted in February 2015 using the search terms edoxaban (ordu-176b) and atrial fibrillation, deep vein thrombosis, pulmonary embolism, or venous thromboembolism. Bibliographies of all retrieved articles were reviewed. All references included were published between 1998 and 2015.. All studies that included humans and contained data describing the use of edoxaban for either stroke prevention in patients with NVAF or the treatment of venous thromboembolism (VTE) were reviewed.. Edoxaban is a target-specific oral anticoagulant, specifically a factor Xa inhibitor. It has been studied in 4 major randomized controlled trials for the prevention of stroke and systemic embolism in patients with NVAF. One randomized controlled trial was conducted for the treatment of VTE. Edoxaban demonstrated noninferiority of the primary efficacy end point compared with warfarin for both approved indications. The most common adverse effect is bleeding, similar to other anticoagulants. A dosing limitation exists related to patients treated for NVAF with creatinine clearance >95 mL/min; these patients experienced decreased efficacy.. Edoxaban is a safe and effective anticoagulant to reduce the risk of stroke in patients with NVAF and for the treatment of VTE.

Topics: Atrial Fibrillation; Drug Interactions; Factor Xa Inhibitors; Hemorrhage; Humans; Pyridines; Randomized Controlled Trials as Topic; Stroke; Thiazoles; Venous Thromboembolism

As non-valvular atrial fibrillation (AF) brings a risk of stroke, oral anticoagulants (OAC) are recommended. In 'real world' clinical practice, many patients (who may be, or perceived to be, intolerant of OACs) are either untreated or are treated with anti-platelet agents. We hypothesised that edoxaban has a better net clinical benefit (NCB, balancing the reduction in stroke risk vs increased risk of haemorrhage) than no treatment or anti-platelet agents. We performed a network meta-analysis of published data from 24 studies of 203,394 AF patients to indirectly compare edoxaban with aspirin alone, aspirin plus clopidogrel, and placebo. Edoxaban 30 mg once daily significantly reduced the risk of all stroke, ischaemic stroke and mortality compared to placebo and aspirin. Compared to aspirin plus clopidogrel, there was a lower risk of intra-cranial haemorrhage (ICH). Edoxaban 60 mg once-daily had a reduced risk of any stroke and systemic embolism compared to placebo, aspirin, and aspirin plus clopidogrel. Mortality rates for both edoxaban doses were estimated to be lower compared to any anti-platelet, and significantly lower compared to placebo. With overall reduced risk of ischemic stroke and ICH, both edoxaban doses bring a NCB of mean (SD) 1.68 (0.15) saved events per 100 patients per year compared to anti-platelet drugs in a clinical trial population. The NCB was demonstrated to be lower, at 0.77 (0.12) events saved (p< 0.01) when modeled to data from a 'real world' cohort of AF patients. In conclusion, edoxaban is likely to provide even better protection from stroke and ICH than placebo, aspirin alone, or aspirin plus clopidogrel in both clinical trial populations and unselected community populations. Both edoxaban doses would also bring a positive NCB compared to anti-platelet drugs or placebo/non-treatment based on 'real world' data.

Topics: Anticoagulants; Aspirin; Atrial Fibrillation; Brain Ischemia; Cerebral Hemorrhage; Clopidogrel; Drug Synergism; Drug Therapy, Combination; Embolism; Factor Xa Inhibitors; Humans; Mortality; Numbers Needed To Treat; Observational Studies as Topic; Platelet Aggregation Inhibitors; Pyridines; Randomized Controlled Trials as Topic; Risk; Risk Assessment; Stroke; Thiazoles; Thrombophilia; Ticlopidine; Vitamin K

Edoxaban is an oral once-daily factor Xa inhibitor with a predictable anticoagulant effect. After oral administration, edoxaban is rapidly absorbed from the gastrointestinal tract, reaching the peak plasma concentrations at 1-2 h. Oral bioavailability is 62% in healthy subjects and the terminal half-life is approximately 10-14 h. Edoxaban has been extensively studied in three clinical scenarios. In ENGAGE AF-TIMI 48, edoxaban was at least as effective as warfarin, but with a marked lesser risk of bleeding. In the Hokusai-VTE study, edoxaban was as effective as warfarin for the prevention of recurrent venous thromboembolism (VTE) in patients with deep venous thrombosis, pulmonary embolism, or both, but with a lesser risk of bleeding. In the STARS program, edoxaban was more effective for the prevention of VTE after knee or hip arthroplasty than low-dose enoxaparin, without an increased bleeding risk. In this review, the available clinical evidence about edoxaban is updated.

Topics: Administration, Oral; Arthroplasty, Replacement, Hip; Atrial Fibrillation; Clinical Trials as Topic; Factor Xa Inhibitors; Humans; Pyridines; Stroke; Thiazoles; Venous Thromboembolism

This study was designed to compare efficacy and safety among novel oral anticoagulants (NOACs), which have not been directly compared in randomized control trials to date.. We performed network meta-analyses of randomized control trials in preventing thromboembolic events and major bleeding in patients with atrial fibrillation. PubMed, Embase, and the Cochrane Database of Systematic Reviews for published studies and various registries of clinical trials for unpublished studies were searched for 2002-2013. All phase III randomized controlled trials (RCTs) of NOACs (apixaban, edoxaban, dabigatran, rivaroxaban), idraparinux, and ximelagatran were reviewed.. A systematic literature search identified nine phase III RCTs for primary analyses. The efficacy of each NOAC was similar with respect to our primary composite endpoint following adjustment for open label designs [odds ratios (ORs) versus vitamin K antagonists: apixaban 0.79; dabigatran 150mg 0.77; edoxaban 60mg 0.87; rivaroxaban 0.86] except for dabigatran 110mg and edoxaban 30mg. Apixaban and edoxaban 30mg and 60mg had significantly fewer major bleeding events than dabigatran 150mg, ricvaroxaban, and vitamin K antagonists. All NOACs were similar in reducing secondary endpoints with the exception of dabigatran 110mg and 150mg which were associated with a significantly greater incidence of myocardial infarction compared to apixaban, edoxaban 60mg, and rivaroxaban.. Our indirect comparison with adjustment for study design suggests that the efficacy of the examined NOACs is similar across drugs, but that some differences in safety and risk of myocardial infarction exist, and that open label study designs appear to overestimate safety and treatment efficacy. Differences in study design should be taken into account in the interpretation of results from RCTs of NOACs.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Dabigatran; Hemorrhage; Humans; Myocardial Infarction; Odds Ratio; Oligosaccharides; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiazoles; Thromboembolism; Treatment Outcome; Vitamin K

Oral anticoagulation therapy is the mainstay of stroke prevention in nonvalvular atrial fibrillation patients. Vitamin K antagonists (such as warfarin) have been effective conventional oral anticoagulants for several decades. However, due to their limitations in clinical use, several nonvitamin K antagonist oral anticoagulants (NOACs, including dabigatran, rivaroxaban, apixaban and edoxaban) have been developed. Nonetheless, no head to head trials have been performed to directly compare these NOACs in patient cohorts. In this review article, two direct factor Xa inhibitors, apixaban and edoxaban, are briefly described with focus on their pharmacokinetic and pharmacodynamic profiles, plus drug interactions. Moreover, both efficacy and safety will be discussed based on the available data from the large Phase III clinical trials and indirect comparison studies.

Topics: Atrial Fibrillation; Factor Xa Inhibitors; Humans; Pyrazoles; Pyridines; Pyridones; Stroke; Thiazoles

No pooled analysis has been undertaken to assess the efficacy and safety of the non-vitamin K antagonist oral anticoagulants (NOACs) compared with warfarin in the subgroup of patients with atrial fibrillation (AF) and heart failure (HF), including edoxaban data from recent randomized controlled trials (RCTs).. Comprehensive literature searches were conducted using the Cochrane Library, MEDLINE, and Scopus databases from inception to April 2015. Statistical analyses were performed using RevMan 5.3 software.. Four RCTs were included: 19 122 of 32 512 AF patients with HF were allocated to a NOAC (13 384 receiving single-/high-dose NOAC regimens), and 13 390 to warfarin. Among AF patients with HF, single/high-dose NOACs significantly reduced the risk of stroke/systemic embolic (SE) events by 14% [odds ratio0.86, 95% confidence interval (CI) 0.76-0.98), and had a 24% lower risk of major bleeding(OR 0.76, 95% CI 0.67-0.86). For low-dose NOAC regimens, comparable efficacy to warfarin for stroke or SE events (OR 1.02, 95% CI 0.86-1.21) and a non-significant trend for lower major bleeding was observed. Regardless of high- or low-dose NOAC, the incidences of both major bleeding and stroke/SE in AF patients with HF were similar to those without HF. Atrial fibrillation patients with HF on NOACs had a 41% lower risk of intracranial haemorrhage compared with those without HF (OR 0.59, 95% CI 0.40-0.87).. Among AF patients with HF, single-/high-dose NOAC regimens have a better efficacy and safety profile, but low-dose regimens had similar efficacy and safety to warfarin. NOACs were similarly effective or even safer (less intracranial haemorrhage) in AF patients with HF compared with those without HF.

Topics: Anticoagulants; Atrial Fibrillation; Heart Failure; Hemorrhage; Humans; Pyridines; Randomized Controlled Trials as Topic; Risk Adjustment; Stroke; Thiazoles; Treatment Outcome; Warfarin

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Factor Xa Inhibitors; Humans; Pyrazoles; Pyridines; Pyridones; Risk Factors; Rivaroxaban; Stroke; Thiazoles; Warfarin

The factor Xa inhibitor edoxaban (Lixiana(®)) is a new direct oral anticoagulant recently approved in the EU for the prevention of stroke and systemic embolic events (SEE) in patients with nonvalvular atrial fibrillation and one or more risk factors. In the large, randomized, double-blind, double-dummy, ENGAGE AF-TIMI 48 trial, oral edoxaban dosages of 30 and 60 mg once daily for a median treatment duration of 907 days in patients with moderate-to-high-risk nonvalvular atrial fibrillation were noninferior to warfarin for the incidence of first stroke or SEE. Both high-dose and low-dose edoxaban were associated with significantly lower rates than warfarin of major bleeding, including intracranial haemorrhage, and death from cardiovascular causes. Edoxaban has a rapid onset of action, a short half-life, few drug interactions and offers the convenience of oral, once-daily, fixed-dose administration, without the need for coagulation monitoring and without regard to food. Therefore, edoxaban is an effective and well tolerated therapeutic option in patients with nonvalvular atrial fibrillation.

Topics: Anticoagulants; Atrial Fibrillation; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Interactions; Factor Xa Inhibitors; Hemorrhage; Humans; Pyridines; Risk Factors; Stroke; Thiazoles; Warfarin

Four new oral anticoagulants have been approved for reducing stroke risk in patients with nonvalvular atrial fibrillation. Compared with warfarin, these agents offer a more predictable dose response with fewer food and drug interactions and no regular blood monitoring, although some of the drugs have an increased risk of major gastrointestinal bleeding. This article reviews the new drugs.

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Factor Xa Inhibitors; Gastrointestinal Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles

Oral anticoagulation is central to the management of patients with atrial fibrillation (AF) and at least one additional stroke risk factor. For decades, the vitamin K antagonists (e.g. warfarin) remained the only oral anticoagulant available for stroke prevention in AF. The non-vitamin K oral anticoagulants (NOACs) are now available, and these drugs include the direct thrombin inhibitors and factor Xa inhibitors. The latter class includes edoxaban, which has recently been approved for stroke prevention in AF by the United States Food and Drug Administration and the European Medicine Agency. In line with other NOACs, edoxaban avoids the many limitations of warfarin associated with variability of anticoagulation effect and multiple food and drug interactions.. In this review, the currently available evidence on edoxaban in patients with non-valvular AF is discussed. The pharmacology, efficacy and safety, and current aspects of use of edoxaban in patients with non-valvular AF for stroke and thromboembolism prevention are reviewed.. Phase III trials on edoxaban for stroke prevention in non-valvular AF confirms non-inferiority of edoxaban compared to well-managed warfarin both in terms of efficacy and safety. Currently ongoing and future trials as well as real-world data are warranted to confirm its effectiveness and safety for chronic anticoagulation and improve evidence in other areas which are lacking evidence where NOAC use remains controversial.

Topics: Atrial Fibrillation; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Embolism; Factor Xa Inhibitors; Humans; Pyridines; Risk; Stroke; Thiazoles; Thromboembolism; Vitamin K; Warfarin

Dabigatran (a direct thrombin inhibitor) and rivaroxaban, apixaban, and edoxaban (direct activated factor X inhibitors) are increasingly being used in clinical practice. Compared with vitamin K antagonists, they are more convenient, do not require laboratory monitoring, have limited drug and food interactions, and have fixed dosages suitable for most patients. But the shortcomings of these agents can jeopardize their efficacy and increase the risk of bleeding. Their future role in preventing and treating thromboembolic disease will depend on building clinical experience, but current evidence indicates that they are reasonable alternatives to vitamin K antagonists.

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Venous Thrombosis

During the past four years the phase III trials on stroke prophylaxis in atrial fibrillation and on treatment of venous thromboembolism have been completed for four new oral anticoagulants - dabigatran, apixaban, edoxaban and rivaroxaban. The studies have revealed advantages in terms of a reduced risk of bleeding, most importantly of intracranial bleeding. These anticoagulants also have favourable pharmacokinetics, eliminating the need for routine laboratory monitoring and dose adjustments. There are, however, some differences between the drugs in certain subsets of patients, according to patient characteristics or to indication for treatment. These features are reviewed here. The management of patients in association with invasive procedures or major bleeding is also discussed. Finally, a strategy of how to select patients for warfarin or the new anticoagulants and thereafter possibly also among the latter is outlined.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Clinical Trials, Phase III as Topic; Dabigatran; Hemorrhage; Humans; Morpholines; Patient Selection; Pyrazoles; Pyridines; Pyridones; Risk; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Treatment Outcome; Venous Thromboembolism; Warfarin

Four recently introduced new oral anticoagulants (dabigatran, rivaroxaban, apixaban and edoxaban) have been shown to be at least as efficacious and safe as warfarin for stroke prevention in patients with atrial fibrillation in their respective trials. The first three have been approved, while edoxaban is awaiting regulatory approval. Several guidelines have endorsed the approved new oral anticoagulants over warfarin because of their favourable risk-benefit ratio, low propensity for food and drug interactions, and lack of requirement for routine coagulation monitoring. In this invited review, we summarise the results of the four studies and discuss widely held conclusions. We take a step further and discuss how differences in study design, analysis plan, and unexpected events affect the interpretation of the study results. Finally, we take our re-interpretation of study results and discuss how they might impact clinical practice and anticoagulant choice for patients.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Data Interpretation, Statistical; Humans; Morpholines; Practice Guidelines as Topic; Pyrazoles; Pyridines; Pyridones; Research Design; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Treatment Outcome

Heparins and vitamin K antagonists (VKA) used commonly are the standard treatment of venous and arterial thromboses. They are very efficient and safe, but have some limitations: iatrogenicity, laboratory monitoring, parenteral use for heparins and fondaparinux. Nowadays, four new inhibitors of factor Xa are used orally (rivaroxaban, apixaban, edoxaban, betrixaban), and they are at least as efficient as heparins and vitamin K antagonists. The objective is to substitute these indirect inhibitors of factor Xa (heparins, low molecular weight heparins and fondaparinux) in the prevention of venous and arterial thromboembolic episodes. The new direct inhibitors do not require routine laboratory monitoring of blood coagulation. They inhibit the extrinsic and the intrinsic pathways of blood coagulation. Rivaroxaban and apixaban are efficacious and safe in the prevention of cerebral infarcts in patients with non-valvular fibrillation. Apixaban is another direct inhibitor of factor Xa used orally which is developed in the same indications as rivaroxaban. Edoxaban and betrixaban are also in development. The objective of this work is to study the pharmacodynamic, pharmacokinetic, the efficacy and safety of these four oral direct factor Xa inhibitors.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Benzamides; Blood Coagulation; Embolism; Factor Xa Inhibitors; Hemorrhage; Hemostatics; Humans; Morpholines; Postoperative Complications; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Thrombophilia; Thrombosis

Anticoagulation for stroke prevention in atrial fibrillation (AF) is effective. Pivotal trials RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE-AF TIMI 48 tested novel agents against warfarin (W). In RE-LY, an open-label trial, dabigatran 150 mg BID (D150) was superior (35%) and 110 mg BID (D110) was noninferior to W. D150 reduced ischemic strokes by 25% and intracerebral bleeds by 74%, but increased major GI bleeds by 0.5 % per year. In ROCKET AF, a double-blind study, rivaroxaban 20 mg daily, downtitrated to 15 mg daily (if CrCl was <49) was noninferior for efficacy and safety, with an increase in GI bleeds. In ARISTOTLE, a double-blind study, apixaban 5 mg BID (downtitrated to 2.5 mg BID if two of the following were present: age, >80; weight, <60 kg; or serum creatinine, >1.5 mg) was superior for safety (31%), efficacy (21%), and all-cause mortality (11%). In ENGAGE-AF TIMI 48, edoxaban 60 mg once daily (30 mg once daily if CrCl 30-50 ml/min, weight <60 kg, or concomitant verapamil or quinidine) was noninferior to W for efficacy, but reduced major bleeding (20%). To translate clinical trials to practice, understanding the disease and each anticoagulant is essential. For all novel agents, rapid anticoagulation, absence of monitoring, and a short half-life differentiate them from W. Bleed rates were either noninferior or lower than for W, without an antidote. Patient compliance is critical. Knowledge of renal function is essential and maintaining patients on therapy is key.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Translational Research, Biomedical; Treatment Outcome

The introduction of direct oral anticoagulants (OACs) for the treatment and prevention of thromboembolic disease represents a shift from the traditional vitamin K antagonist-based therapies, which have been the mainstay of treatment for almost 60 years. A challenge for hospital formularies will be to manage the use of direct OACs from hospital to outpatient settings. Three direct OACs-apixaban, dabigatran and rivaroxaban-are widely approved across different indications, with rivaroxaban approved across the widest breadth of indications. A fourth direct OAC, edoxaban, has also completed phase III trials. Implementation of these agents by physicians will require an understanding of the efficacy and safety profile of these drugs, as well as an awareness of renal function, comedication use, patient adherence and compliance. Optimal implementation of direct OACs in the hospital setting will provide improved patient outcomes when compared with traditional anticoagulants and will simplify the treatment and prevention of thromboembolic diseases.

Topics: Acute Kidney Injury; Administration, Oral; Anticoagulants; Atrial Fibrillation; Clinical Trials, Phase III as Topic; Dabigatran; Drug Administration Schedule; Hemorrhage; Humans; Medication Adherence; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thromboembolism; Treatment Outcome

Stroke is the most feared complication of atrial fibrillation but for over fifty years there has been no simple, effective preventative alternative to warfarin. The development of new risk algorithms such as CHADSVASC has resulted in more patients being recommended anticoagulation therapy. Fixed dose oral anticoagulation is a landmark in drug development for atrial fibrillation. The differences between the drugs are discussed and the trial data examined. As we enter this new frontier of therapy, there is no doubt that these drugs will transform the delivery of anticoagulation for patients with atrial fibrillation.

Topics: Administration, Oral; Animals; Anticoagulants; Atrial Fibrillation; Benzimidazoles; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes

Warfarin has remained the mainstay of stroke prevention in atrial fibrillation for the past 60 years. Recently, two new groups of novel oral anticoagulants- direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) have shown promising results in well conducted clinical trials in terms of efficacy, safety and convenience of usage. However, in real world practice these novel agents come with their share of side effects and drawbacks which the prescribing physician must be aware about. In this review we discuss the role of these novel agents in real world clinical practice - their advantages, disadvantages and future directions.

Topics: Animals; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Drug Discovery; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Warfarin

The availability of 4 non-vitamin K oral anticoagulants (NOACs), that is, dabigatran, rivaroxaban, apixaban, and edoxaban, has changed the landscape of stroke prevention in patients with atrial fibrillation. This review article provides an overview of the 4 phase III studies that have compared these NOACs, examining major outcomes of efficacy and safety. A range of practical questions relating to the NOACs have emerged, including topics such as patient selection, treating patients with renal impairment, treating elderly patients, and combining anticoagulant therapy with antiplatelet drugs. We also address the interaction of various patient characteristics with the treatments and suggest the features can assist the physician in the choice of a particular NOAC for a particular patient(s).

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Drug Administration Schedule; Drug Therapy, Combination; Humans; Morpholines; Patient Preference; Platelet Aggregation Inhibitors; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Research Design; Rivaroxaban; Stroke; Thiazoles; Thiophenes

Venous thromboembolism and atrial fibrillation are among the most common cardiovascular disorders in the United States. For over 50 years, the standard of care has been anticoagulation with vitamin K antagonists. However, the numerous limitations of vitamin K antagonists led to the development of target-specific oral anticoagulants. Dabigatran, rivaroxaban, apixaban, and edoxaban have been shown to be as effective as warfarin in the treatment and prevention of venous thromboembolism and prevention of stroke in nonvalvular atrial fibrillation. This article compares the basic pharmacologic properties of these anticoagulants, reviews the data supporting their use, and discusses practical clinical issues including measurement of the anticoagulation effect, reversal strategies, and management of patients prior to surgery.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Drug Interactions; Humans; Medication Adherence; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Venous Thromboembolism; Warfarin

Until about 4 years ago, warfarin was the only oral anticoagulant approved in the United States, and switching between oral anticoagulants has become an option since the emergence of the novel oral anticoagulants dabigatran, rivaroxaban, and apixaban. What are the reasons one may switch between the agents and how is this done? Discussed in this article are the 4 agents approved in the United States, their characteristics, reasons one may switch, and methods for conversion. After a thorough search of original trial data and recent expert review articles, we have summarized the most recent recommendations below and briefly discuss upcoming oral anticoagulants that show promise.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; United States; Warfarin

Vitamin K antagonists (VKAs) have long been the standard of care for treatment of venous thromboembolism (VTE), and thromboprophylaxis in atrial fibrillation (AF). Despite their efficacy, their use requires frequent monitoring and is complicated by drug-drug interactions and the need to maintain a narrow therapeutic window. Since 2009, novel oral anticoagulants (NOACs), including the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors apixaban, edoxaban, and rivaroxaban, have become alternative options to VKAs owing to their predictable and safe pharmacological profiles. The overall clinical effect of these drugs, which is a balance between ischaemic benefit and bleeding harm, varies according to the clinical scenario. As adjunctive therapy to dual antiplatelet therapy in patients with acute coronary syndrome, NOACs are associated with incremental bleeding risks and modest benefits. For treatment of VTE, NOACs have a safer profile than VKAs and a similar efficacy. In thromboprophylaxis in AF, NOACs are associated with the greatest benefits by reducing both ischaemic events and haemorrhagic complications and might reduce mortality compared with VKAs. The role of NOACs continues to evolve as these drugs are evaluated in different patient populations, including those with renal impairment or with AF and undergoing percutaneous coronary intervention.

Topics: Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Ischemia; Morpholines; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Venous Thromboembolism

For the last decades vitamin K antagonists have been the most effective anticoagulant treatment of atrial fibrillation. New molecules are being designed, mainly due to the great amount of disadvantages in the management of conventional anticoagulation. Dabigatran, rivaroxaban and apixaban will soon be available as an alternative to warfarin/acenocumarol. All of them have demonstrated to be non-inferior to warfarin in preventing stroke and systemic embolism, with even dabigatran 150 mg bid and apixaban being superior. They have also a lower risk of bleeding, especially regarding severe/fatal and intracranial hemorrhages. This is a real revolution. The advance of these new anticoagulants will be limited only by the higher cost, and will progressively become the protagonists of oral anticoagulation in patients with nonvalvular atrial fibrillation.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzimidazoles; Benzylamines; beta-Alanine; Dabigatran; Embolism; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Treatment Outcome; Warfarin

Stroke is the most feared complication among patients with atrial fibrillation. Oral anticoagulation therapy with vitamin K antagonists (VKAs) has been the gold standard for stroke prevention for the past 60 years. However, VKA therapy has many downsides, including risk for bleeding, a narrow therapeutic window, and the need for frequent monitoring, as well as numerous diet and lifestyle considerations that make its use cumbersome. Thus, development of new drugs that can preserve the benefits of VKAs while eliminating the negative aspects of VKA therapy has been enthusiastically sought. This article reviews the anticoagulant agents that are clinically available or under development as alternatives to VKAs for stroke prevention in patients with nonvalvular atrial fibrillation.

Topics: Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Warfarin

Anticoagulants can complicate the approach to the management of patients undergoing operative interventions. We review new anticoagulants that have been introduced recently to the market or that are undergoing investigations for treatment of nonvalvular atrial fibrillation and venous thromboembolism prophylaxis: Dabigatran, rivaroxaban, apixiban, and edoxaban.

Topics: Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Blood Loss, Surgical; Clinical Trials as Topic; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Surgical Procedures, Operative; Thiazoles; Thiophenes; Venous Thromboembolism; Warfarin

Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice and is associated with a nearly 5-fold increase in the risk of stroke. Warfarin has been the cornerstone of treatment to reduce stroke risk in AF patients for decades. Although effective in preventing thrombosis, warfarin is difficult to manage and is associated with a 1% to 7% yearly risk of major hemorrhage. Until recently, there were no effective oral alternatives to warfarin. Dabigatran etexilate, a direct thrombin inhibitor, was approved in 2010 for the reduction of stroke and systemic embolism in patients with nonvalvular AF, and the factor Xa inhibitor rivaroxaban was approved for a similar indication in 2011. Other late-stage orally administered agents that may be approved for this indication include apixaban and edoxaban; others at earlier stages of development will be discussed in this review as well. Nonpharmacological approaches to stroke prevention include left atrial appendage removal, ligation, or occlusion. This review examines advances in the management of stroke risk in AF patients, focusing on recently marketed and late-stage modalities. The advent of alternatives to warfarin for reducing stroke risk in AF patients may improve physicians' ability to offer safe and effective stroke prevention in all AF patients.

Topics: Anticoagulants; Antithrombin Proteins; Atrial Appendage; Atrial Fibrillation; Benzimidazoles; Chemoprevention; Dabigatran; Fibrinolytic Agents; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Warfarin

As the population ages, the prevalence of atrial fibrillation (AF) continues to rise. The most feared complication of this common cardiac arrhythmia is cardioembolic stroke. Strokes related to AF are associated with greater morbidity and mortality than ischemic strokes of most other etiologies and impose a substantial economic burden on healthcare systems around the world. Until recently, warfarin was the sole anticoagulant proven effective for stroke prevention patients with AF at elevated risk, but its narrow therapeutic margin and variable dose response limited clinical utility. The emergence of new anticoagulants that offer equal or superior efficacy, greater safety and the convenience of fixed oral dosing may make warfarin the less preferred option. This review provides an update on recent advancements in antithrombotic therapy for stroke prevention in patients with AF.

Topics: Anticoagulants; Antithrombins; Aspirin; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Clopidogrel; Dabigatran; Hemorrhage; Humans; Morpholines; Practice Guidelines as Topic; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Thrombolytic Therapy; Ticlopidine; Warfarin

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Elective Surgical Procedures; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Ischemic Attack, Transient; Medical Records; Morpholines; Perioperative Period; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Thromboembolism

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Electric Countershock; Factor Xa Inhibitors; Humans; Kidney Failure, Chronic; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Warfarin

The last decade has seen the evaluation of several new oral anticoagulants that directly target thrombin or activated factor X (FXa). All demonstrate a rapid onset of action, a low potential for food and drug interactions, and a predictable anticoagulant effect that obviates the need for routine coagulation monitoring. Those agents at the most advanced stages of clinical development are a direct thrombin inhibitor, dabigatran, and direct FXa inhibitors, rivaroxaban and apixaban. Dabigatran and rivaroxaban are approved in more than 70 countries for prevention of venous thromboembolism in patients undergoing elective hip or knee arthroplasty, and apixaban is being considered for approval by regulatory agencies for this indication. Dabigatran was shown in a large phase III trial to be more effective and safer than warfarin for the prevention of stroke or systemic embolism in patients with atrial fibrillation and has recently been approved for this indication. Edoxaban, an oral FXa inhibitor, is also being evaluated in phase III clinical trials. This review summarizes the pharmacology, clinical trial results, and future role of the new oral anticoagulants in clinical practice.

Topics: Acute Coronary Syndrome; Amidines; Anticoagulants; Atrial Fibrillation; Azetidines; Benzimidazoles; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Thrombin; Thromboembolism; Treatment Outcome; Vitamin K

Daiichi Sankyo is developing edoxaban tosylate (DU 176b; DU-176; DU-176b; DU176b) as an orally active direct factor Xa inhibitor for the prevention of stroke and the prevention and treatment of venous thromboembolism. Two dosing regimens of edoxaban tosylate are being compared with warfarin over 24 months in the ENGAGE AF TIMI 48 trial (NCT00781391) in over 21 000 patients with atrial fibrillation in North and South America, Africa, Asia, Europe, Australia, and New Zealand. Edoxaban tosylate is also being compared with warfarin in the treatment and prevention of recurrent thromboembolic events in approximately 7500 patients with deep-vein thrombosis and/or pulmonary embolism in the HOKUSAI VTE trial (NCT00986154) being conducted in 40 countries. This review discusses the development history and scientific profile of this new compound.

Topics: Animals; Clinical Trials as Topic; Factor Xa; Factor Xa Inhibitors; Humans; Pyridines; Stroke; Thiazoles; Venous Thromboembolism

Anticoagulant therapy, known as warfarin, has been underused despite its marked benefit from embolic prevention. The intricate maintenance has made physicians constrained the use of warfarin for the many decades. Facing the 21(st) century, several new anticoagulants which inhibit single coagulant factor, such as activated factor X (Xa) or activated factor II (thrombin), has been developed. We now have selective thrombin inhibitor, dabigatran, already rolled out in clinical practice around the world. Among these drugs, four new Xa inhibitors are in final developing stage. This article reviewed the current status of new Xa inhibitors. Rivaroxaban leads the other Xa inhibitors in distribution. The phase III clinical study called ROCKET AF study had been completed and recently published. Statistical non-inferiority was clearly established compared to regular warfarin therapy. The Japanese rolled J-ROCKET AF study with 1,000 patients and the usage of reduced dose of rivaroxaban has made a similar outcome and safety end points compared to the initial ROCKET AF study. ARISTOTLE study, a phase III clinical study of apixaban has also been finished this year and will be presented soon. A phase III study of using edoxaban, a Japanese manufactured Xa inhibitor, named ENGAGE AF-TIMI 48 will be completed by next year. Darexaban, another Japan-made Xa inhibitor is in its preparation of phase III trial following favorable results of its late phase II study (OPAL-2). Having every trial with its favorable outcome, multiple alternatives of Xa inhibitors will be out in practice in no distant future. In addition, we must be aware to have a deliberate evaluation for each result, even pharmacological profiles of each Xa inhibitors with a 12 hour half-life period shows similarity, the difference in twice-daily dosing with once a day, or the difference in severity of patients' atrial fibrillation risk factor each trial contains might affect the results of phase III trials.

Topics: Anticoagulants; Atrial Fibrillation; Azepines; Benzamides; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes

Prevention of stroke and systemic emboli is paramount in the management of atrial fibrillation. Although warfarin is the predominant anticoagulant used in patients with atrial fibrillation, it has significant limitations that have impeded appropriate use of stroke prophylaxis in eligible patients with atrial fibrillation. Consequently, much research has been focused on finding an alternative to warfarin. We review the potential alternatives in development and evaluate the current evidence concerning their safety and efficacy.. Oral direct factor Xa inhibitors are potentially well tolerated and effective replacements for warfarin. These agents do not require cofactors and offer selective inhibition at a critical step of amplification in the coagulation cascade. Multiple direct anti-factor Xa agents are currently undergoing evaluation in phase I, II, and III trials. Early results suggest that these novel anticoagulants have favorable pharmacokinetic and pharmacodynamic profiles with minimal-to-no requirements for therapeutic monitoring. Two direct factor Xa inhibitors are emerging from phase II trials (betrixaban and YM150) and three are being evaluated in phase III trials (apixaban, edoxaban, and rivaroxaban) for the prevention of stroke and systemic emboli in patients with atrial fibrillation. The phase III trials of apixaban and rivaroxaban have completed enrollment and are in the follow-up phase.. Given the growing population of patients with atrial fibrillation, there is a great interest in finding new therapies for oral anticoagulation. The direct factor Xa inhibitors may offer several promising alternatives to warfarin therapy.

Topics: Anticoagulants; Atrial Fibrillation; Benzamides; Factor Xa Inhibitors; Fibrinolytic Agents; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Thromboembolism; Warfarin

Anticoagulation could not be currently stopped even after successful thoracoscopic ablation of atrial fibrillation for at least 2 months. The aim of this study is to compare the safety and efficacy outcomes between a new oral anticoagulant and warfarin after thoracoscopic ablation. This trial was a single-center, prospective, randomized controlled study comparing edoxaban and warfarin in patients undergoing thoracoscopic ablation of atrial fibrillation. This study enrolled 60 patients randomly assigned into 2 groups. The primary endpoint was efficacy outcomes, including stroke and systemic thromboembolic events. The secondary endpoint was safety outcomes including major bleeding and pericarditis. The patients were evaluated at discharge, 2 weeks, 3 months, and 6 months postoperatively. No stroke and thromboembolic events were noted in both treatment groups during the follow-up period. During the 6 months follow-up period, 4 (13%) of 30 patients in the edoxaban group experienced minor bleeding events, whereas none were noted in the warfarin group. Five anticoagulation-related events (bleeding, and prolongation of international normalized ratio), including pericarditis, were noted in both the edoxaban and warfarin groups. No statistically significant difference existed between the 2 groups. In conclusion, this study showed the comparable results of edoxaban to warfarin during the window period of post-thoracoscopic ablation of atrial fibrillation. Moreover, anticoagulation-related events were rather affected by patient factors and not by the anticoagulant type.

Topics: Anticoagulants; Atrial Fibrillation; Hemorrhage; Humans; Pericarditis; Prospective Studies; Stroke; Thromboembolism; Treatment Outcome; Vitamin K; Warfarin

The neutrophil-to-lymphocyte ratio (NLR) is the ratio between neutrophil and lymphocyte counts measured in peripheral blood. NLR is easily calculable based on a routine blood test available worldwide and may reflect systemic inflammation. However, the relationship between NLR and clinical outcomes in atrial fibrillation (AF) patients is not well-described.. We calculated NLR at baseline in ENGAGE AF-TIMI 48, a randomized trial comparing edoxaban versus warfarin in patients with AF followed for 2.8 years (median). The association of baseline NLR with major bleeding events, major adverse cardiac events (MACE), cardiovascular death, stroke/systemic embolism, and all-cause mortality were calculated.. The median baseline NLR in 19,697 patients was 2.53 (interquartile range 1.89-3.41). NLR was associated with major bleeding events (HR 1.60; 95% CI 1.41-1.80), stroke/systemic embolism (HR 1.25; 95% CI, 1.09-1.44), MI (HR 1.73; 95% CI 1.41-2.12), MACE (HR 1.70; 95% CI 1.56-1.84), CV (HR 1.93; 95% CI 1.74-2.13) and all-cause mortality (HR 2.00; 95% CI 1.83-2.18). The relationships between NLR and outcomes remained significant after adjustment for risk factors. Edoxaban consistently reduced major bleeding. MACE, and CV death across NLR groups vs. warfarin.. NLR represents a widely available, simple, arithmetic calculation that could be immediately and automatically reported during a white blood cell differential measurement to identify patients with AF at increased risk of bleeding, CV events, and mortality.

Topics: Anticoagulants; Atrial Fibrillation; Embolism; Factor Xa Inhibitors; Hemorrhage; Humans; Lymphocytes; Neutrophils; Stroke; Treatment Outcome; Warfarin

Device-detected atrial high-rate episodes (AHREs) are atrial arrhythmias detected by implanted cardiac devices. AHREs resemble atrial fibrillation but are rare and brief. Whether the occurrence of AHREs in patients without atrial fibrillation (as documented on a conventional electrocardiogram [ECG]) justifies the initiation of anticoagulants is not known.. We conducted an event-driven, double-blind, double-dummy, randomized trial involving patients 65 years of age or older who had AHREs lasting for at least 6 minutes and who had at least one additional risk factor for stroke. Patients were randomly assigned in a 1:1 ratio to receive edoxaban or placebo. The primary efficacy outcome was a composite of cardiovascular death, stroke, or systemic embolism, evaluated in a time-to-event analysis. The safety outcome was a composite of death from any cause or major bleeding.. The analysis population consisted of 2536 patients (1270 in the edoxaban group and 1266 in the placebo group). The mean age was 78 years, 37.4% were women, and the median duration of AHREs was 2.8 hours. The trial was terminated early, at a median follow-up of 21 months, on the basis of safety concerns and the results of an independent, informal assessment of futility for the efficacy of edoxaban; at termination, the planned enrollment had been completed. A primary efficacy outcome event occurred in 83 patients (3.2% per patient-year) in the edoxaban group and in 101 patients (4.0% per patient-year) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.60 to 1.08; P = 0.15). The incidence of stroke was approximately 1% per patient-year in both groups. A safety outcome event occurred in 149 patients (5.9% per patient-year) in the edoxaban group and in 114 patients (4.5% per patient-year) in the placebo group (hazard ratio, 1.31; 95% CI, 1.02 to 1.67; P = 0.03). ECG-diagnosed atrial fibrillation developed in 462 of 2536 patients (18.2% total, 8.7% per patient-year).. Among patients with AHREs detected by implantable devices, anticoagulation with edoxaban did not significantly reduce the incidence of a composite of cardiovascular death, stroke, or systemic embolism as compared with placebo, but it led to a higher incidence of a composite of death or major bleeding. The incidence of stroke was low in both groups. (Funded by the German Center for Cardiovascular Research and others; NOAH-AFNET 6 ClinicalTrials.gov number, NCT02618577; ISRCTN number, ISRCTN17309850.).

Topics: Aged; Anticoagulants; Arrhythmias, Cardiac; Atrial Fibrillation; Double-Blind Method; Electrodes, Implanted; Embolism; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Risk Factors; Stroke

Topics: Aged; Aortic Valve; Aortic Valve Stenosis; Atrial Fibrillation; Female; Hemorrhage; Humans; Hypertension; Male; Prospective Studies; Risk Factors; Stroke; Transcatheter Aortic Valve Replacement; Treatment Outcome

ENVISAGE-TAVI AF (Edoxaban versus Standard of Care and Their Effects on Clinical Outcomes in Patients Having Undergone Transcatheter Aortic Valve Implantation-Atrial Fibrillation; NCT02943785) was a prospective, randomized, open-label trial comparing non-vitamin K oral anticoagulant (NOAC) edoxaban with vitamin K antagonists (VKAs) in patients with atrial fibrillation after successful transcatheter aortic valve replacement (TAVR). The effect of edoxaban- or VKA-based therapy on patient-reported outcomes remains unknown, as most studies focus on efficacy and safety. Pre-TAVR patient-reported expectations and post-TAVR Treatment Satisfaction and Convenience with edoxaban or VKA treatment (at months 3 and 12) were analyzed using the Perception of Anticoagulation Treatment Questionnaire (PACT-Q). This analysis included randomized and dosed patients with an evaluable PACT-Q1 assessment at baseline and ≥1 postbaseline assessment (PACT-Q2). Subanalyses included patients stratified by pre-TAVR anticoagulant (NOAC, VKA, no NOAC/VKA). Edoxaban- (n = 585) and VKA-treated (n = 522) patients had similar baseline characteristics and treatment expectations. Pre-TAVR anticoagulant use did not affect treatment expectations. After TAVR, edoxaban-treated patients had significantly higher Treatment Satisfaction and Convenience scores compared with VKA-treated patients at all time points (p <0.001 for all). Among edoxaban-treated patients, those who received VKAs pre-TAVR were significantly more satisfied with treatment than those who received NOACs (p <0.001) or no NOACs/VKAs (p = 0.003); however, there was no significant difference in the perception of convenience (p = 0.927 and p = 0.092, respectively). Conversely, among VKA-treated patients, the type of anticoagulant used pre-TAVR did not affect Treatment Satisfaction or Convenience scores post-TAVR. In conclusion, patients with atrial fibrillation who received edoxaban post-TAVR reported significantly higher Treatment Satisfaction and Convenience scores compared with those who received VKAs, resulting in a clinically meaningful difference between treatment groups.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Fibrinolytic Agents; Humans; Patient Satisfaction; Prospective Studies; Stroke; Transcatheter Aortic Valve Replacement; Treatment Outcome; Vitamin K

Early warfarin anticoagulation is recommended in patients undergoing surgical bioprosthetic valve implantation or valve repair. It is unclear whether non-vitamin K antagonist oral anticoagulants can be a full alternative to warfarin. This study aimed to compare efficacy and safety of edoxaban with warfarin in patients early after surgical bioprosthetic valve implantation or valve repair.. The Explore the Efficacy and Safety of Edoxaban in Patients after Heart Valve Repair or Bioprosthetic Valve Replacement study was a prospective, randomized (1:1), open-label, clinical trial conducted from December 2017 to September 2019. Patients were randomly assigned to receive edoxaban (60 mg or 30 mg once daily) or warfarin for the first 3 months after surgical bioprosthetic valve implantation or valve repair. The primary efficacy outcome was a composite of death, clinical thromboembolic events, or asymptomatic intracardiac thrombosis. The primary safety outcome was the occurrence of major bleeding.. Of 220 participants, 218 (109 per group) were included in the modified intention-to-treat analysis. The primary efficacy outcome occurred in 4 patients (3.7%) taking warfarin and none taking edoxaban (risk difference, -0.0367; 95% confidence interval, -0.0720 to -0.0014; P < .001 for noninferiority). The primary safety outcome occurred in 1 patient (0.9%) taking warfarin and 3 patients (2.8%) taking edoxaban (risk difference, 0.0183; 95% confidence interval, -0.0172 to 0.0539; P = .013 for noninferiority).. Edoxaban is noninferior to warfarin for preventing thromboembolism and is potentially comparable for risk of major bleeding during the first 3 months after surgical bioprosthetic valve implantation or valve repair.

Topics: Anticoagulants; Atrial Fibrillation; Hemorrhage; Humans; Prospective Studies; Stroke; Thromboembolism; Treatment Outcome; Warfarin

Elderly atrial fibrillation (AF) patients with risk factors of bleeding are often considered ineligible for standard oral anticoagulants (OACs). The Edoxaban Low-Dose for EldeR CARE AF patients (ELDERCARE-AF) trial recently showed that edoxaban 15 mg/day was superior to placebo for preventing stroke or systemic embolism and did not result in a significantly higher incidence of major bleeding. Our aim was to investigate a real-world cohort of AF patients similar to the ELDERCARE-AF cohort, with regard to the impact of direct oral anticoagulant (DOAC) use compared to non-OAC use, in relation to clinical outcomes.. From 1 January 2012 to 31 December 2016, 15 183 AF patients aged ≥80 years (mean age 86.63 years [SD 4.79]; 48.7% male) with a congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and prior stroke or transient ischemic attack (CHADS2) score ≥2 who met the enrolment criteria (generally similar to ELDERCARE-AF) were identified from the Taiwan National Health Insurance Research Database. Patients were categorized into two groups according to their stroke prevention strategies, i.e. without OACs (n = 9084) and DOACs (n = 6099). Patients receiving DOACs were further stratified into reduced-dose- or full-dose-regimen groups. Compared with the non-OAC group as a reference, DOAC use (whether at reduced dose or full dose) was associated with a lower risk of ischaemic stroke (adjusted hazard ratio [aHR] 0.77, 95% confidence interval [CI] 0.67-0.88) and all-cause mortality (aHR 0.39, 95% CI 0.37-0.42), while the risks of intracranial haemorrhage and major bleeding were similar. The risks of composite outcomes of 'ischaemic stroke or mortality' (aHR 0.42, 95% CI 0.40-0.45) and 'ischaemic stroke or major bleeding or mortality' (aHR 0.49, 95% CI 0.46-0.52) were significantly lower with DOAC use. When compared with the non-OAC group as the reference group, DOACs (whether reduced dose or full dose) showed a positive net clinical benefit. The results were generally consistent even after propensity matching.. In routine clinical care, DOACs (whether reduced or full dose) were associated with a lower risk of ischaemic stroke, mortality, and the composite endpoint, when compared with non-OAC use in high-risk elderly AF patients at increased bleeding risk. Our findings provide complementary 'real-world' data to support the generalizability of the results of the ELDERCARE-AF trial to other DOACs in daily clinical practice.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Female; Hemorrhage; Humans; Ischemic Stroke; Male; Stroke

Edoxaban 60 mg is approved for stroke prevention in patients with atrial fibrillation (AF) not fulfilling any dose-reduction criteria. As edoxaban is partially renally cleared (≈50%), this study compared pharmacokinetics (PK) and pharmacodynamics of edoxaban 60 mg once daily with edoxaban 75 mg once daily in patients with AF with high renal clearance (creatinine clearance > 100 mL/min) over 12 months. Primary PK and pharmacodynamics end points were plasma edoxaban exposure and anti-factor Xa (FXa) concentration. A population PK model estimated edoxaban exposure at steady state. Efficacy and safety outcomes included composites of stroke, transient ischemic attack, systemic embolism, and major and clinically relevant nonmajor bleeding. Of 607 patients, 303 and 304 were randomized to edoxaban 60 and 75 mg, respectively. Edoxaban 75 mg provided ≈25% higher exposure than 60 mg. This increase was accurately depicted in the population PK model; anti-factor Xa concentration correlated with edoxaban exposure. Rates of composite and individual outcomes were similarly low between doses. In conclusion, the 25% increase in edoxaban dose (60-75 mg) resulted in ≈25% exposure increase in the 75-mg group. Higher exposure was not associated with reduced stroke risk in patients with AF with high renal clearance.

Topics: Anticoagulants; Atrial Fibrillation; Creatinine; Double-Blind Method; Humans; Pyridines; Stroke; Thiazoles; Treatment Outcome; Warfarin

In patients with atrial fibrillation (AF), peripheral artery disease (PAD) is associated with higher rates of stroke and bleeding. Both higher dose edoxaban (60/30 mg) and lower dose edoxaban (30/15 mg) were non-inferior to warfarin for stroke and systemic embolism (SSE) and significantly reduced major bleeding in AF patients in the global study to assess the safety and effectiveness of edoxaban vs standard practice of dosing with warfarin in patients with atrial fibrillation (ENGAGE AF-TIMI 48) trial. Whether the efficacy and safety of these dosing strategies vs. warfarin are consistent in patients with AF and PAD has not been described.. Of 21 105 patients with AF randomized to warfarin, edoxaban 60/30 mg, or edoxaban 30/15 mg, 841 were identified with PAD. Endpoints included major adverse cardiovascular events (MACEs), SSE, and major bleeding. Patients with PAD had higher risk of MACEs [adjusted hazard ratio (HRadj) 1.33, 95% confidence interval (CI) 1.12-1.57, P = 0.001] and cardiovascular (CV) death (HRadj 1.49, 95% CI 1.21-1.83, P < 0.001) than those without PAD, but not major bleeding. The efficacy of edoxaban 60/30 mg vs. warfarin was consistent regardless of PAD (SSE HR; PAD 1.16, 95% CI 0.42-3.20; no-PAD 0.86, 95% CI 0.74-1.02, P-interaction 0.57) as was major bleeding (PAD 0.96, 95% CI 0.54-1.70; no-PAD 0.80, 95% CI 0.70-0.91, P-interaction 0.54). Edoxaban 30/15 mg was inferior for SSE, with significant heterogeneity when stratified by PAD status (P-interaction 0.039).. Patients with AF and PAD are at heightened risk of MACEs and CV death vs. those without PAD. The efficacy and safety of edoxaban 60/30 mg vs. warfarin in AF are consistent regardless of PAD; however, edoxaban 30/15 mg is inferior for stroke prevention in AF patients with PAD. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT00781391.

Topics: Anticoagulants; Atrial Fibrillation; Embolism; Factor Xa Inhibitors; Hemorrhage; Humans; Peripheral Arterial Disease; Pyridines; Stroke; Thiazoles; Warfarin

To compare the efficacy and safety of edoxaban vs warfarin in high-risk subgroups.. While underuse of anticoagulation in high-risk patients with AF remains common, substitution of effective and safer alternatives to warfarin, such as edoxaban, represents an opportunity to improve clinical outcomes.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Body Weight; Factor Xa Inhibitors; Humans; Pyridines; Stroke; Thiazoles; Treatment Outcome; Warfarin

Long-term use of oral anticoagulants (OACs) is necessary for stroke prevention in patients with atrial fibrillation (AF). The effectiveness and safety of OACs in extremely older patients (ie, aged 80 years or older) with AF and at high risk of bleeding needs to be elucidated.. To examine the effects of very low-dose edoxaban (15 mg) vs placebo across 3 age strata (80-84 years, 85-89 years, and ≥90 years) among patients with AF who were a part of the Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients (ELDERCARE-AF) trial.. This prespecified subanalysis of a phase 3, randomized, double-blind, placebo-controlled trial was conducted from August 5, 2016, to December 27, 2019. Patients with AF aged 80 years or older who were not considered candidates for standard-dose OACs were included in the study; reasons these patients could not take standard-dose OACs included low creatinine clearance (<30 mL per minute), low body weight (≤45 kg), history of bleeding from critical organs, continuous use of nonsteroidal anti-inflammatory drugs, or concomitant use of antiplatelet drugs. Eligible patients were recruited randomly from 164 hospitals in Japan and were randomly assigned 1:1 to edoxaban or placebo.. Edoxaban (15 mg once daily) or placebo.. The primary efficacy end point was the composite of stroke or systemic embolism. The primary safety end point was International Society on Thrombosis and Hemostasis-defined major bleeding.. A total of 984 patients (mean [SD] age: age group 80-84 years, 82.2 [1.4] years; age group 85-89 years, 86.8 [1.4] years; age group ≥90 years, 92.3 [2.1] years; 565 women [57.4%]) were included in this study. In the placebo group, estimated (SE) event rates for stroke or systemic embolism increased with age and were 3.9% (1.2%) per patient-year in the group aged 80 to 84 years (n = 181), 7.3% (1.7%) per patient-year in the group aged 85 to 89 years (n = 184), and 10.1% (2.5%) per patient-year in the group aged 90 years or older (n = 127). A 15-mg dose of edoxaban consistently decreased the event rates for stroke or systemic embolism with no interaction with age (80-84 years, hazard ratio [HR], 0.41; 95% CI, 0.13-1.31; P = .13; 85-89 years, HR, 0.42; 95% CI, 0.17-0.99; P = .05; ≥90 years, HR, 0.23; 95% CI, 0.08-0.68; P = .008; interaction P = .65). Major bleeding and major or clinically relevant nonmajor bleeding events were numerically higher with edoxaban, but the differences did not reach statistical significance, and there was no interaction with age. There was no difference in the event rate for all-cause death between the edoxaban and placebo groups in all age strata.. Results of this subanalysis of the ELDERCARE-AF randomized clinical trial revealed that among Japanese patients aged 80 years or older with AF who were not considered candidates for standard OACs, a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism consistently across all 3 age strata, including those aged 90 years or older, albeit with a higher but nonstatistically significant incidence of bleeding.. ClinicalTrials.gov Identifier: NCT02801669.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Embolism; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Pyridines; Stroke; Thiazoles; Warfarin

High adherence to oral anticoagulants is essential for stroke prevention in patients with atrial fibrillation (AF). We developed a smartphone application (app) that pushes alarms for taking medication and measuring blood pressure (BP) and heart rate (HR) at certain times of the day. In addition to drug alarms, the habit of measuring one's BP and HR may reinforce drug adherence by improving self-awareness of the disease. This pilot study aims to test the feasibility and efficacy of the smartphone app-based intervention for improving drug adherence in patients with AF.. A total of 10 university hospitals in Korea will participate in this randomised control trial. Patients with AF, being treated with edoxaban for stroke prevention will be included in this study. Total of 500 patients will be included and the patients will be randomised to the conventional treatment group (250 patients) and the app conditional feedback group (250 patients). Patients in the app conditional feedback group will use the medication reminder app for medication and BP check alarms. The automatic BP machine will be linked to the smartphone via Bluetooth. The measured BP and HR will be updated automatically on the smartphone app. The primary endpoint is edoxaban adherence by pill count measurement at 3 and 6 months of follow-up. Secondary endpoints are clinical composite endpoints including stroke, systemic embolic event, major bleeding requiring hospitalisation or transfusion, or death during the 6 months. As of 24t November 2021, 80 patients were enrolled.. This study was approved by the Seoul National University Bundang Hospital Institutional Review Board and will be conducted according to the principles of the Declaration of Helsinki. The study results will be published in a reputable journal.. KCT0004754.

Topics: Atrial Fibrillation; Humans; Mobile Applications; Pilot Projects; Pyridines; Randomized Controlled Trials as Topic; Smartphone; Stroke; Thiazoles

Japanese patients undergoing transcatheter aortic valve replacement (TAVR) are often female and have a small body size, potentially impacting bleeding risk with antithrombotic therapy. Outcomes of direct oral anticoagulant use in these patients with atrial fibrillation (AF) need to be clarified.Methods and Results: This prespecified analysis included Japanese patients from ENVISAGE-TAVI AF, a prospective, randomized, open-label, adjudicator-masked trial that compared treatment with edoxaban and vitamin K antagonists (VKAs) in patients with AF after TAVR. The primary efficacy and safety outcomes were net adverse clinical events (NACE; composite of all-cause death, myocardial infarction, ischemic stroke, systemic embolic event, valve thrombosis, and International Society on Thrombosis and Haemostasis [ISTH]-defined major bleeding) and ISTH-defined major bleeding, respectively. Intention-to-treat (ITT) and on-treatment analyses were performed. Overall, 159 Japanese patients were enrolled (edoxaban group: 82, VKA group: 77) and followed for on average 483 days. Mean patient age was 83.8 years; 52.2% were female. In the ITT analysis, NACE rates were 10.9%/year with edoxaban and 12.5%/year with VKA (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.38-1.90); major bleeding occurred in 8.9%/year and 7.3%/year, respectively (HR, 1.17; 95% CI, 0.45-3.05). In edoxaban- and VKA-treated patients, rates of ischemic stroke were 1.8%/year and 1.0%/year, respectively; fatal bleeding rates were 0.9%/year and 2.0 %/year. On-treatment results were similar to ITT.. In Japanese patients with AF after successful TAVR, edoxaban and VKA treatment have similar safety and efficacy profiles.

Topics: Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Female; Fibrinolytic Agents; Hemorrhage; Humans; Ischemic Stroke; Japan; Male; Prospective Studies; Stroke; Transcatheter Aortic Valve Replacement; Treatment Outcome; Vitamin K

The prevalence of atrial fibrillation (AF) increases with age and is more common in frail patients. However, data are lacking on outcomes of oral anticoagulants (OACs) in very elderly patients with AF with frailty, who are ineligible for standard anticoagulant treatment.. To compare very-low-dose edoxaban (15 mg daily) vs placebo across frailty status, including each of 5 frailty assessment parameters, among patients with AF involved in the ELDERCARE-AF (Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients) trial.. This is a cohort study using data from ELDERCARE-AF, a multicenter, randomized, double-blind, placebo-controlled phase 3 study of Japanese patients with AF aged 80 years or older who were ineligible for OACs at doses approved for stroke prevention because of their high bleeding risks. Eligible patients were randomly assigned (1:1) to receive edoxaban or placebo. The study duration was from August 5, 2016, to November 5, 2019, with the last patient followed up on December 27, 2019. Data analysis was performed from February 2021 to February 2022.. Edoxaban (15 mg) once daily or placebo.. The primary efficacy end point was the composite of stroke or systemic embolism, and the primary safety end point was major bleeding.. A total of 984 patients were randomly assigned to treatment (492 each to the edoxaban and placebo groups); 944 patients (402 frail patients [42.6%]; 542 nonfrail patients [57.4%]; mean [SD] age, 86.6 [4.3] years; 541 women [57.3%]) were included in this analysis. In the placebo group, the estimated event rates (SE) for stroke or systemic embolism were 7.1% (1.6%) per patient-year in the frail group and 6.1% (1.3%) per patient-year in the nonfrail group. Edoxaban was associated with lower event rates for stroke or systemic embolism with no interaction with frailty status or frailty assessment parameters. Major bleeding and major or clinically relevant nonmajor bleeding events were both numerically higher in the edoxaban group than in the placebo group, and no heterogeneity was observed with frailty status. Although both all-cause death and net clinical composite outcome occurred more frequently in the frail group than in the nonfrail group, there was no association with frailty status between the edoxaban and placebo groups.. Regardless of frailty status, among Japanese patients with AF aged 80 years or older who were ineligible for standard OACs, once-daily 15-mg edoxaban was associated with reduced incidence of stroke or systemic embolism and may be a suitable treatment option for these patients.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cohort Studies; Embolism; Factor Xa Inhibitors; Female; Frail Elderly; Frailty; Hemorrhage; Humans; Pyridines; Stroke; Thiazoles

The Atrial fibrillation Better Care (ABC) pathway is endorsed by guidelines to improve care of patients with atrial fibrillation (AF). However, whether the benefit of ABC pathway-concordant care is consistent across anticoagulants remains unclear. We assessed the association between ABC-concordant care and outcomes in this post hoc analysis from the ENGAGE AF-TIMI 48 trial, which was reported prior to the initial description of the ABC pathway.. Patients were retrospectively classified as receiving ABC-concordant care based on optimal anticoagulation, adequate rate control, management of co-morbidities and lifestyle measures. Associations between ABC-concordance and outcomes were assessed with adjustment for components of the CHA2DS2-VASc and HAS-BLED scores. Of 20 926 patients, 7915 (37.8%) satisfied criteria of ABC-concordant care, which was associated with significantly lower incidence of stroke or systemic embolic event [stroke/SEE: hazard ratio (HRadj): 0.54; 95% confidence interval (CI): 0.47-0.63], major bleeding (HRadj 0.66; 95% CI: 0.58-0.75), major adverse cardiac events (HRadj 0.53; 95% CI: 0.48-0.58), primary net clinical outcome (composite of stroke/SEE, major bleeding or death; HRadj 0.61; 95% CI: 0.56-0.65), cardiovascular (CV) hospitalization (HRadj 0.78; 95% CI: 0.74-0.83), CV death (HRadj 0.52; 95% CI: 0.46-0.58), and all-cause mortality (HRadj 0.56; 95% CI: 0.51-0.62), P < 0.001 for each. These associations were qualitatively consistent for both edoxaban and warfarin and across patient subgroups.. Atrial fibrillation Better Care pathway-concordant care is associated with reductions across multiple CV endpoints and all-cause mortality, with benefit in edoxaban- and warfarin-treated patients and across patient subgroups. Increasing implementation of ABC-concordant care may improve clinical outcomes of patients with AF irrespective of anticoagulant.

Topics: Anticoagulants; Atrial Fibrillation; Critical Pathways; Factor Xa Inhibitors; Hemorrhage; Humans; Retrospective Studies; Stroke; Treatment Outcome; Warfarin

Background We investigated the predictors related to major bleeding events during treatment with edoxaban 15 mg in patients aged ≥80 years with nonvalvular atrial fibrillation and high bleeding risk, for whom standard oral anticoagulants are inappropriate, focusing on standard laboratory tests related to bleeding. Methods and Results This was a prespecified subanalysis of the on-treatment analysis set of the ELDERCARE-AF (Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients) trial. Major bleeding was the primary safety end point. The event rates were calculated according to prespecified characteristics at baseline. A total of 984 Japanese patients were randomly assigned to edoxaban 15 mg or placebo (n=492, each). During the study period, 20 and 11 major bleeding events occurred in the edoxaban and placebo groups, respectively. The adjusted analysis revealed that hemoglobin <12.3 g/dL (adjusted hazard ratio [aHR], 3.57 [95% CI, 1.10-11.55]) and prothrombin time ≥12.7 seconds; (aHR, 2.89 [95% CI, 1.05-8.02]) independently predicted major bleeding, while creatinine clearance <30 mL/min showed a tendency towards an increase in major bleeding (aHR, 2.68; 95% CI, 0.96-7.46). In patients treated with edoxaban lacking these 3 risk factors, no major bleeding occurred; major bleeding event rates increased with each risk factor. Patients with 3 risk factors were significantly more likely to have a major bleeding event at 11.05%/year (HR, 7.15 [95% CI, 1.92-26.71]). Conclusions In elderly patients with nonvalvular atrial fibrillation with high bleeding risk, baseline hemoglobin <12.3 g/dL, prothrombin time ≥12.7 seconds, and creatinine clearance <30 mL/min may predict major bleeding during treatment with edoxaban 15 mg. Registration URL: ELDERCARE-AF https://www.clinicaltrials.gov; Unique number: NCT02801669.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Creatinine; Double-Blind Method; Factor Xa Inhibitors; Hemorrhage; Humans; Pyridines; Stroke; Thiazoles; Warfarin

Current guidelines recommend an oral anticoagulant (OAC) monotherapy in patients with nonvalvular atrial fibrillation (NVAF) and stable coronary artery disease (CAD) 1 year postpercutaneous coronary intervention (PCI). It might be possible to shorten the time for de-escalation from a dual therapy to monotherapy, but data regarding de-escalation to an edoxaban monotherapy are lacking. This study aimed to assess the clinical safety of an edoxaban monotherapy in patients with NVAF and stable CAD.. A multicenter, prospective, randomized, open-label, and parallel group study was established to investigate the safety of an edoxaban monotherapy in patients with NVAF and stable CAD including over 6 months postimplantation of a third-generation DES and 1 year postimplantation of other stents (PRAEDO AF study). Between March 2018 and June 2020, 147 patients from 8 institutions in Japan were randomized to receive either an edoxaban monotherapy (. Major or clinically significant bleeding occurred in 2 patients in the monotherapy group (1.67% per patient-year) and in 5 patients in the combination therapy group (4.28% per patient-year) (hazard ratio, 0.39; 95% confidence interval, 0.08-2.02). There was no incidence of a myocardial infarction, stent thrombosis, unstable angina requiring revascularization, ischemic stroke, systemic stroke, or hemorrhagic stroke in either of the groups.. The edoxaban monotherapy was shown to have acceptable clinical safety in patients with NVAF and stable CAD. The study was registered with the Japan Registry of Clinical Trials (jRCTs031180119).

Topics: Anticoagulants; Atrial Fibrillation; Coronary Artery Disease; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prospective Studies; Stroke

Chronic thromboembolic pulmonary hypertension (CTEPH) is a complication of prior pulmonary thromboembolism (PE), caused by incomplete clot dissolution after PE. In patients with CTEPH, lifelong anticoagulation is mandatory to prevent recurrence of PE and secondary in situ thrombus formation. Warfarin, a vitamin K antagonist, is commonly used for anticoagulation in CTEPH based on historical experience and evidence. The anticoagulant activity of warfarin is affected by food and drug interactions, requiring regular monitoring of prothrombin time. The lability of anticoagulant effect often results in haemorrhagic and thromboembolic complications. Thus, lifelong warfarin is a handicap in terms of safety and convenience. Currently, the use of direct oral anticoagulants (DOACs) in CTEPH has increased with the advent of four DOACs. The safety of DOACs is superior to warfarin, with less intracranial bleeding in patients with non-valvular atrial fibrillation and venous thromboembolism. Edoxaban, the latest DOAC, also has proven efficacy and safety for those diseases in two large clinical trials; the ENGAGE-AF trial and HOKUSAI-VTE trial. The present trial seeks to evaluate whether edoxaban is non-inferior to warfarin in preventing worsening of CTEPH.. The KABUKI trial (is an investigator-initiated, multicentre, phase 3, randomised, single-blind, parallel-group, warfarin-controlled, non-inferiority trial to evaluate the efficacy and safety of edoxaban versus warfarin (vitamin K Antagonist) in subjects with chronic thromBoembolic pUlmonary hypertension taking warfarin (vitamin K antagonIst) at baseline) is designed to prove the non-inferiority of edoxaban to warfarin in terms of efficacy and safety in patients with CTEPH.. This study is approved by the Institutional Review Board of each participating institution. The findings will be published in a peer-reviewed journal, including positive, negative and inconclusive results.. NCT04730037.. This paper was written per the study protocol V.4.0, dated 29 January 2021.

Topics: Anticoagulants; Atrial Fibrillation; Humans; Hypertension, Pulmonary; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Single-Blind Method; Stroke; Venous Thromboembolism; Vitamin K; Warfarin

Diabetes mellitus is an independent risk factor for stroke and atrial fibrillation. Therefore, the risk/benefit profile of the oral factor Xa inhibitor edoxaban stratified by diabetes is of clinical interest.. 21,105 patients enrolled in ENGAGE AF-TIMI 48 were stratified into 2 pre-specified groups: without (N = 13,481) and with diabetes (N = 7,624).. On average, patients with diabetes were younger, and had a higher body mass index, CHA. Patients with diabetes in ENGAGE AF-TIMI 48 had higher bleeding risk, but after adjustment similar stroke risk, compared to those without diabetes. The higher-dose edoxaban regimen had similar efficacy compared to warfarin, while reducing bleeding and cardiovascular mortality, irrespective of diabetes.

Topics: Anticoagulants; Atrial Fibrillation; Diabetes Mellitus; Factor Xa Inhibitors; Humans; Pyridines; Stroke; Thiazoles; Treatment Outcome

Edoxaban, alongside other direct oral anticoagulants (DOAC), is increasingly used for prevention of thromboembolism, including stroke. Despite DOAC therapy, however, annual stroke rate in patients with atrial fibrillation remains 1-2%. Rapid exclusion of relevant anticoagulation is necessary to guide thrombolysis or reversal therapy but, so far, no data exists on the effect of edoxaban on available point-of-care test systems (POCT). To complete our previous investigation on global coagulation-POCT for the detection of DOAC, we evaluated whether CoaguChek®-INR (CC-INR) is capable of safely ruling out edoxaban concentrations above the current treatment thresholds of 30/50 ng/mL in a blood sample. We studied patients receiving a first dose of edoxaban; excluding subjects receiving other anticoagulants. Six blood samples were collected from each patient: before drug intake, 0.5, 1, 2 and 8 h after intake, and at trough (24 h). CC-INR and mass spectrometry for edoxaban concentrations were performed for each time-point. One hundred and twenty blood samples from 20 patients contained 0-302 ng/mL of edoxaban. CC-INR ranged from 0.9 to 2.3. Pearson's correlation coefficient showed strong correlation between CC-INR and edoxaban concentrations (r = 0.73, p < 0.001). Edoxaban concentrations > 30 and > 50 ng/mL were ruled out by CC-INR ≤ 1.0 and ≤ 1.1, respectively, with high specificity (> 95%), and a sensitivity of 44% (95%-confidence interval: 30-59%) and 86% (74-93%), respectively. Our study represents the first evaluation of coagulation-POCT in edoxaban-treated patients. CC-POCT is suitable to safely exclude clinically relevant edoxaban concentrations prior to thrombolysis, or guide reversal therapy in stroke patients.

Topics: Aged; Atrial Fibrillation; Blood Coagulation; Blood Coagulation Tests; Drug Monitoring; Factor Xa Inhibitors; Female; Humans; International Normalized Ratio; Male; Middle Aged; Point-of-Care Testing; Prospective Studies; Pyridines; Stroke; Thiazoles

The ongoing prospective, single-arm, observational, phase 4 ETNA-AF Europe study is collecting real-world data about the safety and, secondarily, the effectiveness and therapeutic adherence of newly prescribed edoxaban for non-valvular atrial fibrillation in Europe.. At the end of enrollment in 2018, 13 980 subjects were included, of whom 3509 were Italian. Of them, 3341 (95.2%) had follow-up data available at 1 year.. Their mean age was 75 ± 9.3 years, with 56.9% being ≥75 years old. The CHA2DS2-VASc score was ≥4 in 1380 (41.3%) patients. Overall, 662 patients (19.7%) were judged as "frail" by the investigators. Edoxaban 30 mg/day was given to 1048 (31.4%) subjects, who were older with more comorbidities and a lower estimated creatinine clearance than those prescribed the 60 mg/day dose. Overall, the rates of bleeding and thromboembolic events were low: major bleeding was 1.63%/year, intracranial hemorrhage 0.16%/year, stroke or systemic embolism 0.50%/year and all-cause mortality 3.72%/year. Rates were higher in subjects ≥75 years or with a CHA2DS2-VASc score ≥4 and in frail individuals. Remarkably, there was a trend for no increase in intracranial bleeding with more advanced age.. These findings confirm the favorable safety and effectiveness profile of edoxaban in atrial fibrillation patients in routine clinical care in Italy.

Topics: Age Factors; Aged; Aged, 80 and over; Atrial Fibrillation; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Female; Follow-Up Studies; Hemorrhage; Humans; Italy; Male; Medication Adherence; Middle Aged; Prospective Studies; Pyridines; Stroke; Thiazoles; Thromboembolism

To compare the safety and efficacy of edoxaban combined with P2Y12 inhibition following percutaneous coronary intervention (PCI) in patients with atrial fibrillation (AF) presenting with an acute coronary syndrome (ACS) or chronic coronary syndrome (CCS).. In this pre-specified sub-analysis of the ENTRUST-AF PCI trial, participants were randomly assigned 1:1 to edoxaban- or vitamin K antagonist (VKA)-based strategy and randomization was stratified by ACS (edoxaban n = 388, VKA n = 389) vs. CCS (edoxaban n = 363, VKA = 366). Participants received edoxaban 60 mg once-daily plus a P2Y12 inhibitor for 12 months, or VKA combined with a P2Y12 inhibitor and aspirin 100 mg (for 1-12 months). The primary bleeding endpoint at 12 months occurred in 59 (15.2%) vs. 79 (20.3%) ACS patients [hazard ratio (HR): 0.73, 95% confidence interval (CI): 0.59-1.02, P = 0.063], and in 69 (19.0%) vs. 73 (19.9%) CCS patients (HR: 0.94, 95%CI: 0.68-1.31, P = 0.708) with edoxaban- and VKA-based therapy, respectively [P for interaction (P-int) = 0.2741]. The main secondary endpoint (composite of CV death, myocardial infarction, stroke, systemic embolic events, or definite stent thrombosis) in ACS patients was 33 (8.5%) vs. 28 (7.2%) (HR: 1.16, 95%CI: 0.70-1.92), compared with 16 (4.4%) vs. 18 (4.9%) (HR: 0.91, 95%CI: 0.47-1.78) CCS patients with edoxaban and VKA-based therapy, respectively (P-int = 0.5573).. In patients with AF who underwent PCI, the edoxaban-based regimen, as compared with VKA-based regimen, provides consistent safety and similar efficacy for ischaemic events in patients with AF regardless of their clinical presentation.

Topics: Acute Coronary Syndrome; Anticoagulants; Atrial Fibrillation; Fibrinolytic Agents; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Pyridines; Stroke; Thiazoles; Treatment Outcome

Implementation of appropriate oral anticoagulant treatment for the prevention of stroke in very elderly patients with atrial fibrillation is challenging because of concerns regarding bleeding.. We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled, event-driven trial to compare a once-daily 15-mg dose of edoxaban with placebo in elderly Japanese patients (≥80 years of age) with nonvalvular atrial fibrillation who were not considered to be appropriate candidates for oral anticoagulant therapy at doses approved for stroke prevention. The primary efficacy end point was the composite of stroke or systemic embolism, and the primary safety end point was major bleeding according to the definition of the International Society on Thrombosis and Haemostasis.. A total of 984 patients were randomly assigned in a 1:1 ratio to receive a daily dose of 15 mg of edoxaban (492 patients) or placebo (492 patients). A total of 681 patients completed the trial, and 303 discontinued (158 withdrew, 135 died, and 10 had other reasons); the numbers of patients who discontinued the trial were similar in the two groups. The annualized rate of stroke or systemic embolism was 2.3% in the edoxaban group and 6.7% in the placebo group (hazard ratio, 0.34; 95% confidence interval [CI], 0.19 to 0.61; P<0.001), and the annualized rate of major bleeding was 3.3% in the edoxaban group and 1.8% in the placebo group (hazard ratio, 1.87; 95% CI, 0.90 to 3.89; P = 0.09). There were substantially more events of gastrointestinal bleeding in the edoxaban group than in the placebo group. There was no substantial between-group difference in death from any cause (9.9% in the edoxaban group and 10.2% in the placebo group; hazard ratio, 0.97; 95% CI, 0.69 to 1.36).. In very elderly Japanese patients with nonvalvular atrial fibrillation who were not appropriate candidates for standard doses of oral anticoagulants, a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism and did not result in a significantly higher incidence of major bleeding than placebo. (Funded by Daiichi Sankyo; ELDERCARE-AF ClinicalTrials.gov number, NCT02801669.).

Topics: Aged, 80 and over; Atrial Fibrillation; Double-Blind Method; Embolism; Factor Xa Inhibitors; Female; Follow-Up Studies; Hemorrhage; Humans; Incidence; Male; Patient Dropouts; Pyridines; Stroke; Thiazoles

We aimed to assess the safety of edoxaban in combination with P2Y12 inhibition in patients with atrial fibrillation who had percutaneous coronary intervention (PCI).. ENTRUST-AF PCI was a randomised, multicentre, open-label, non-inferiority phase 3b trial with masked outcome evaluation, done at 186 sites in 18 countries. Patients had atrial fibrillation requiring oral anticoagulation, were aged at least 18 years, and had a successful PCI for stable coronary artery disease or acute coronary syndrome. Participants were randomly assigned (1:1) from 4 h to 5 days after PCI using concealed, stratified, and blocked web-based central randomisation to either edoxaban (60 mg once daily) plus a P2Y12 inhibitor for 12 months or a vitamin K antagonist (VKA) in combination with a P2Y12 inhibitor and aspirin (100 mg once daily, for 1-12 months). The edoxaban dose was reduced to 30 mg per day if one or more factors (creatinine clearance 15-50 mL/min, bodyweight ≤60 kg, or concomitant use of specified potent P-glycoprotein inhibitors) were present. The primary endpoint was a composite of major or clinically relevant non-major (CRNM) bleeding within 12 months. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of their assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02866175, is closed to new participants, and follow-up is completed.. From Feb 24, 2017, through May 7, 2018, 1506 patients were enrolled and randomly assigned to the edoxaban regimen (n=751) or VKA regimen (n=755). Median time from PCI to randomisation was 45·1 h (IQR 22·2-76·2). Major or CRNM bleeding events occurred in 128 (17%) of 751 patients (annualised event rate 20·7%) with the edoxaban regimen and 152 (20%) of 755 patients (annualised event rate 25·6%) patients with the VKA regimen; hazard ratio 0·83 (95% CI 0·65-1·05; p=0·0010 for non-inferiority, margin hazard ratio 1·20; p=0·1154 for superiority).. In patients with atrial fibrillation who had PCI, the edoxaban-based regimen was non-inferior for bleeding compared with the VKA-based regimen, without significant differences in ischaemic events.. Daiichi Sankyo.

Topics: Acute Coronary Syndrome; Aged; Atrial Fibrillation; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Pyridines; Stents; Stroke; Thiazoles; Vitamin K

Data on the comparison between uninterrupted and interrupted by one dose strategies for direct oral anticoagulant (DOAC) use during the periprocedural period of atrial fibrillation (AF) ablation are scarce. The purpose of this study is to investigate the feasibility of uninterrupted DOAC strategy by evaluating the incidence of silent stroke (SS) and perioperative trends in coagulation markers compared with the interrupted strategy.. We randomly divided 200 consecutive patients receiving DOACs, who underwent AF ablation into uninterrupted group (UG = 100) and interrupted by one dose group (IG = 100). The rate of SS confirmed by post-operative magnetic resonance imaging and periprocedural trends in coagulation markers was investigated. A significant difference in SS incidence was found between the UG and IG (UG 4%, IG 17%, P < 0.005), although there were no differences in the rate of complications including bleeding and symptomatic thrombo-embolic events between the two groups. Intraoperative cardioversion [odds ratio (OR) 7.27, 95% confidence interval (CI) 1.76-30.0; P < 0.01] and the length of procedure time (OR 1.03, 95% CI 1.01-1.05; P < 0.05) independently predicted the occurrence of SS in the IG. A significant increase in prothrombin fragment 1 + 2 (PF1 + 2) values was observed in the IG compared with the UG on the operative and first post-operative days.. Silent stroke incidence in the IG was significantly higher than that in the UG; this seems to be supported by the difference in PF1 + 2 values between the UG and IG. Intraoperative cardioversion and procedure time predicted the occurrence of SS in the IG.

Topics: Adult; Aged; Aged, 80 and over; Asymptomatic Diseases; Atrial Fibrillation; Catheter Ablation; Factor Xa Inhibitors; Female; Humans; Incidence; Magnetic Resonance Imaging; Male; Middle Aged; Peptide Fragments; Perioperative Care; Postoperative Complications; Postoperative Hemorrhage; Prospective Studies; Prothrombin; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles

Pacemaker, implantable cardioverter-defibrillator, and cardiac resynchronization therapy device implantations and generator changes are frequently performed in patients receiving direct oral anticoagulants. In an exploratory analysis, we investigated the outcome of patients undergoing such device procedures in the ENGAGE AF-TIMI 48 trial.. During the trial, 1217 device procedures were performed in 1145 patients, with intervention dates available for 1203 procedures. Two hundred and twenty-five procedures (in 212 patients) were performed >30 days after study drug was stopped and are not included in the event analysis. For most interventions (n = 728, 74%), study drug was interrupted >3 days (median for the entire cohort: 5 days, interquartile range 0-11 days); 250 interventions were performed with ≤3 days study drug interruption. During the first 30 days after the procedure, six strokes/systemic embolic events (SEEs) (three each in the lower-dose edoxaban and warfarin arm) and one major bleeding event (in the lower-dose edoxaban arm) occurred; no stroke/SEEs or major bleeds occurred around the 295 device procedures in the higher-dose edoxaban arm. Two ischaemic and one major bleeding event occurred after the 288 device procedures performed with ≤3 days periprocedural interruption of study drug.. In this first experience of patients undergoing device surgery with edoxaban, a low risk of ischaemic and bleeding events was observed during the first 30 days post-procedure. Our data are in line with current recommendations of no or only brief interruption of non-vitamin K antagonist oral anticoagulants prior to cardiac device surgery.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Cardiac Resynchronization Therapy Devices; Defibrillators, Implantable; Device Removal; Double-Blind Method; Drug Administration Schedule; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Pacemaker, Artificial; Prosthesis Implantation; Pyridines; Risk Assessment; Risk Factors; Stroke; Thiazoles; Time Factors; Treatment Outcome; Warfarin

Prior studies suggested that the risks of ischaemic stroke and bleeding in patients of Asian race with atrial fibrillation (AF) may be higher than that of non-Asians. In the analysis of ENGAGE AF-TIMI 48 trial, we compared clinical outcomes, edoxaban concentration, and anti-factor Xa (anti-FXa) activity, between Asian and non-Asian races.. There were 2909 patients of Asian race and 18 195 non-Asian race in the ENGAGE AF-TIMI 48 trial. The risks of thromboembolism and bleeding events were compared for Asians and non-Asians treated with warfarin. The trough levels of edoxaban concentration and anti-FXa activity were also compared and correlated with the efficacy and safety of edoxaban vs. warfarin. Compared to non-Asian patients, the Asian population was on average 2 years younger and 20 kg lighter. In the warfarin group, the adjusted risk of ischaemic stroke did not differ significantly for patients of Asian and non-Asian race [adjusted hazard ratio (aHR) = 1.12, P = 0.56). Asians treated with warfarin had a higher-adjusted risk of intracranial haemorrhage (ICH: aHR 1.71, P = 0.03) compared with non-Asians. The trough edoxaban concentration and anti-FXa activity were 20-25% lower for Asians compared with non-Asians. Compared to warfarin, higher dose edoxaban significantly reduced ICH while preserving the efficacy of stroke prevention in both Asians and non-Asians. Two of three net clinical outcomes appeared to be more favourably reduced with edoxaban in Asians compared with non-Asians (Pint = 0.063 for primary, 0.037 for secondary, and 0.032 for third net clinical outcomes, respectively).. Compared to warfarin, higher dose edoxaban preserved the efficacy for stroke prevention and was associated with a favourable safety profile for Asians, which may be due to the lower trough edoxaban concentration and anti-FXa activity achieved in patients of Asian race.

Topics: Aged; American Indian or Alaska Native; Anticoagulants; Asian People; Atrial Fibrillation; Black People; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Intracranial Hemorrhages; Male; Middle Aged; Proportional Hazards Models; Pyridines; Stroke; Thiazoles; Treatment Outcome; Warfarin; White People

To investigate the relationship between body mass index (BMI) and outcomes in patients with atrial fibrillation (AF).. In the ENGAGE AF-TIMI 48 trial, patients with AF were randomized to warfarin (international normalized ratio 2.0-3.0) or edoxaban. The cohort (N = 21 028) included patients across BMI categories (kg/m2): underweight (<18.5) in 0.8%, normal (18.5 to <25) in 21.4%, overweight (25 to <30) in 37.6%, moderately obese (30 to <35) in 24.8%, severely obese (35 to <40) in 10.0%, and very severely obese (≥40) in 5.5%. In an adjusted analysis, higher BMI (continuous, per 5 kg/m2 increase) was significantly and independently associated with lower risks of stroke/systemic embolic event (SEE) [hazard ratio (HR) 0.88, P = 0.0001], ischaemic stroke/SEE (HR 0.87, P < 0.0001), and death (HR 0.91, P < 0.0001), but with increased risks of major (HR 1.06, P = 0.025) and major or clinically relevant non-major bleeding (HR 1.05, P = 0.0007). There was a significant interaction between sex and increasing BMI category, with lower risk of ischaemic stroke/SEE in males and increased risk of bleeding in women. Trough edoxaban concentration and anti-Factor Xa activity were similar across BMI groups >18.5 kg/m2, while time in therapeutic range for warfarin improved significantly as BMI increased (P < 0.0001). The effects of edoxaban vs. warfarin on stroke/SEE, major bleeding, and net clinical outcome were similar across BMI groups.. An increased BMI was independently associated with a lower risk of stroke/SEE, better survival, but increased risk of bleeding. The efficacy and safety profiles of edoxaban were similar across BMI categories ranging from 18.5 to >40.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Body Mass Index; Comorbidity; Embolism; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Obesity; Overweight; Proportional Hazards Models; Pyridines; Stroke; Thiazoles; Treatment Outcome; Warfarin

Edoxaban is a direct factor Xa inhibitor approved for stroke prevention in atrial fibrillation (AF). Uninterrupted edoxaban therapy in patients undergoing AF ablation has not been tested.. The ELIMINATE-AF trial, a multinational, multicentre, randomized, open-label, parallel-group study, was conducted to assess the safety and efficacy of once-daily edoxaban 60 mg (30 mg in patients indicated for dose reduction) vs. vitamin K antagonists (VKAs) in AF patients undergoing catheter ablation. Patients were randomized 2:1 to edoxaban vs. VKA. The primary endpoint (per-protocol population) was time to first occurrence of all-cause death, stroke, or International Society of Thrombosis and Haemostasis-defined major bleeding during the period from the end of the ablation procedure to end of treatment (90 days). Overall, 632 patients were enrolled, 614 randomized, and 553 received study drug and underwent ablation; 177 subjects underwent brain magnetic resonance imaging to assess silent cerebral infarcts. The primary endpoint (only major bleeds occurred) was observed in 0.3% (1 patient) on edoxaban and 2.0% (2 patients) on VKA [hazard ratio (95% confidence interval): 0.16 (0.02-1.73)]. In the ablation population (modified intent-to-treat population including patients with ablation), the primary endpoint was observed in 2.7% of edoxaban (N = 10) and 1.7% of VKA patients (N = 3) between start of ablation and end of treatment. There were one ischaemic and one haemorrhagic stroke, both in patients on edoxaban. Cerebral microemboli were detected in 13.8% (16) patients who received edoxaban and 9.6% (5) patients in the VKA group (nominal P = 0.62).. Uninterrupted edoxaban therapy represents an alternative to uninterrupted VKA treatment in patients undergoing AF ablation.

Topics: Aged; Atrial Fibrillation; Catheter Ablation; Cerebral Hemorrhage; Factor Xa Inhibitors; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Postoperative Hemorrhage; Pyridines; Stroke; Thiazoles; Vitamin K

Catheter ablation (CA) has been reported to reduce risk of stroke in patients with nonvalvular atrial fibrillation (NVAF) in retrospective studies. However, the risks and benefits of CA have not been well elucidated in patients with NVAF and who have suffered a recent ischemic stroke in prospective randomized trials. Thus, the aim of the STABLED clinical trial is to investigate the efficacy and safety of CA with anticoagulant therapy using edoxaban in patients with NVAF and a history of recent ischemic stroke.. The STABLED trial is a multicenter, prospective, randomized, open-label, standard medication-controlled study in Japan. The target patient number is 250, comprising 125 patients receiving standard medication and 125 receiving CA. For patients allocated to the CA group, ablation is to be performed between 1 to 6 months from the onset of index stroke. The observation period will be 3 years from the day of random allocation of the final patient to any of the groups. The primary outcome measure is the composite of recurrence of ischemic stroke, systemic embolism, all-cause death, and hospitalization for heart failure.. This study will investigate the effectiveness and safety of CA and basic anticoagulation treatment with edoxaban for patients with NVAF who have suffered a recent ischemic stroke. The aim is to determine the best evidence for an optimal treatment strategy for patients with NVAF and recent stroke.. UMIN000031424/NCT03777631.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Catheter Ablation; Embolism; Female; Humans; Japan; Male; Prospective Studies; Pyridines; Recurrence; Secondary Prevention; Stroke; Thiazoles

Hypertension is a risk factor for both stroke and bleeding in patients with atrial fibrillation. Data are sparse regarding the interaction between blood pressure and the efficacy and safety of direct oral anticoagulants. In the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48), 19,679 patients with atrial fibrillation and hypertension were categorized according to average systolic blood pressure (SBP) and diastolic blood pressure (DBP). The primary efficacy and safety end points were the time to the first stroke or systemic embolic event and the time to the first International Society of Thrombosis and Hemostasis major bleeding event, respectively. Risk was calculated using Cox proportional hazards models based on average SBP and DBP and adjusting for 18 clinical characteristics. The efficacy and safety of a higher dose edoxaban regimen (60/30 mg) versus warfarin were evaluated with stratification by average SBP and DBP. Stroke/systemic embolic event occurred significantly more frequently in patients with elevated average SBP (hazard ratio, 2.01; 95% CI, 1.50-2.70 for SBP ≥150 mm Hg relative to 130-139 mm Hg) or DBP (hazard ratio, 2.36; 95% CI, 1.76-3.16 for DBP ≥90 mm Hg relative to 75-<85 mm Hg). The higher dose edoxaban regimen reduced stroke/systemic embolic event across the full range of SBP (P

Topics: Aged; Aged, 80 and over; Atrial Fibrillation; Comorbidity; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Hypertension; Logistic Models; Male; Patient Safety; Prognosis; Proportional Hazards Models; Pyridines; Risk Assessment; Severity of Illness Index; Stroke; Survival Analysis; Thiazoles; Treatment Outcome; Warfarin

Patients with atrial fibrillation (AF) who interrupt anticoagulation are at high risk of thromboembolism and death.. Interruption of study drug was frequent in patients with AF and was associated with a substantial risk of major cardiac and cerebrovascular events over the ensuing 30 days. This risk was particularly high in patients who interrupted as a result of an adverse event; these patients deserve close monitoring and resumption of anticoagulation as soon as it is safe to do so.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pyridines; Retrospective Studies; Risk Factors; Stroke; Thiazoles; Thromboembolism; Warfarin; Withholding Treatment

Patients with atrial fibrillation (AF) are at an approximately 0.5% to 3% increased risk of thromboembolism during and immediately after catheter ablation. Treatment guidelines recommend periprocedural oral anticoagulation plus unfractionated heparin during ablation. Rivaroxaban and dabigatran are the only non-vitamin K oral anticoagulants for which there are randomized controlled trials assessing uninterrupted anticoagulation in patients undergoing catheter ablation of AF. Edoxaban, a direct factor Xa inhibitor, is noninferior vs warfarin for the prevention of stroke or systemic embolism with less major bleeding in patients with nonvalvular AF. The ELIMINATE-AF (Evaluation of Edoxaban Compared With VKA in Subjects Undergoing Catheter Ablation of Nonvalvular Atrial Fibrillation) trial is a multinational, multicenter, prospective, randomized, open-label, parallel-group, blinded-endpoint evaluation (PROBE) study to assess the safety and efficacy of once-daily edoxaban 60 mg (30 mg in patients indicated for a dose reduction) vs vitamin K antagonists (VKA) in patients with nonvalvular AF undergoing catheter ablation (http://www.ClinicalTrials.gov: NCT02942576). A total of 560 patients are planned for randomization to edoxaban or VKA (2:1 ratio) to obtain 450 patients fully compliant with the protocol. Patients will complete 21 to 28 days of anticoagulation prior to the ablation and a 90-day post-ablation period. The primary efficacy endpoint is the composite of all-cause death, stroke, and major bleeding. The primary safety endpoint is major bleeding. A magnetic resonance imaging substudy will assess the incidence of silent cerebral lesions post-ablation. ELIMINATE-AF will define the efficacy and safety of edoxaban for uninterrupted oral anticoagulation during catheter ablation of AF.

Topics: Anticoagulants; Atrial Fibrillation; Brain Ischemia; Catheter Ablation; Clinical Protocols; Drug Administration Schedule; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Magnetic Resonance Imaging; Male; Prospective Studies; Pyridines; Research Design; Risk Factors; Stroke; Thiazoles; Time Factors; Treatment Outcome; Vitamin K; Warfarin

Peri-operative management of anticoagulated patients with atrial fibrillation (AF) is challenging. To gain information on the peri-operative management of edoxaban, we compared outcomes in patients on warfarin or edoxaban enrolled in ENGAGE AF-TIMI 48 who underwent a surgery or invasive procedure.. Data from patients undergoing their first surgery/procedure were analysed and results compared by anticoagulant (warfarin vs. higher- or lower-dose edoxaban regimen [HDER and LDER, respectively]). Patients were classified by procedural management: anticoagulant interrupted (last dose 4-10 days pre-procedure) or anticoagulant continued (last dose ≤ 3 days pre-procedure). Stroke/systemic embolism (SSE), major bleeding (MB), MB or clinically relevant non-MB (CRNMB) and death were assessed from 7 days pre- until 30 days post-procedure. The chi-square test was used to compare outcomes across treatment groups.. In patients requiring surgery/procedure in ENGAGE AF-TIMI 48, peri-operative rates of SSE, MB and death were not significantly different in patients who received edoxaban or warfarin.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Cardiac Surgical Procedures; Double-Blind Method; Female; Hemorrhage; Humans; Male; Perioperative Care; Postoperative Complications; Pyridines; Stroke; Thiazoles; Treatment Outcome; United States; Warfarin

We previously reported exogenous antifactor Xa (FXa) activity as a pharmacokinetic surrogate marker for edoxaban plasma concentrations. Inhibition of endogenous FXa activity is a more biologically relevant pharmacodynamic measure of edoxaban activity. Here we describe the value of endogenous FXa activity as a pharmacodynamic marker linking edoxaban concentrations and clinical outcomes in the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction Study 48).. In ENGAGE AF-TIMI 48, edoxaban was administered in higher dose (60/30 mg QD) and lower dose (30/15 mg QD) regimens. Both regimens incorporated a 50% dose reduction in patients with characteristics known to increase edoxaban concentration. Pharmacokinetic-pharmacodynamic modeling was performed in a subgroup of 3029 patients who had samples collected for endogenous FXa activity (measured using an assay after endogenous FX was activated with Russell viper venom).. Endogenous FXa activity decreased with increasing edoxaban concentrations of ≤440 ng/mL, indicating that inhibition of endogenous FXa activity is saturated above this concentration threshold. Baseline endogenous FXa activity averaged 92.1±20.9% (relative to normal control samples) and was lower with older age, with lower body weight, and in male patients. Model-predicted 24-hour average percentages of inhibition of endogenous FXa activity were 35.8±5.18, 29.1±3.92, 21.9±3.80, and 16.4±2.70 for the higher dose edoxaban regimen 60 mg, dose-reduced higher dose edoxaban regimen 30 mg, lower dose edoxaban regimen 30 mg, and dose-reduced lower dose edoxaban regimen 15 mg groups, respectively. A greater average percentage of inhibition of endogenous FXa activity was associated with a lower incidence of ischemic stroke or systemic embolism and a higher risk of major bleeding ( P<0.001). In a typical subject, the predicted risks for the 10th and 90th percentiles of inhibition of endogenous FXa activity were 1.04% and 0.57% for incidence of ischemic stroke or systemic embolism and 1.35% and 2.33% for major bleeding, respectively.. The extent of inhibition of endogenous FXa activity is influenced by edoxaban dosing and clinical characteristics, and it is associated with both antithrombotic benefit and risk of bleeding. This approach of linking endogenous FXa activity to clinical outcomes may be used to guide dose selection in future clinical trials, monitor patients in certain clinical scenarios, or refine the doses of oral FXa inhibitors in patients who require precise anticoagulation therapy.. URL: https://www.clinicaltrials.gov . Unique identifier: NCT00781391.

Topics: Aged; Dose-Response Relationship, Drug; Embolism; Factor Xa; Factor Xa Inhibitors; Female; Half-Life; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Pyridines; Risk Factors; Stroke; Thiazoles; Treatment Outcome

Non-vitamin K dependent oral anticoagulants (NOAC) are now widely used in patients with nonvalvular atrial fibrillation (NVAF) for stroke prevention and in patients with venous thromboembolism (VTE) for the treatment and secondary prevention of the disease. Among NOAC, edoxaban demonstrated noninferiority to warfarin for stroke prevention in NVAF and for VTE treatment, with superior safety. EMIT-AF/VTE (Edoxaban Management in Diagnostic and Therapeutic Procedures) (NCT02950168) is a multicenter, prospective, and noninterventional registry study designed to collect detailed information on the periprocedural management of patients with NVAF and VTE receiving edoxaban. The primary objective of EMIT-AF/VTE is to document the periprocedural management of patients receiving edoxaban and to collect data on safety and other outcomes in these patients. The primary safety outcome is the rate of major bleeding. Other assessments include the evaluation of efficacy outcomes, periprocedural dosing, and timing of edoxaban. The observation period will start 5 days prior to the procedure and end 30 days post-procedure. EMIT-AF/VTE will aim to prospectively enroll up to approximately 1400 procedures from Europe. Enrollment commenced in December 2016 and will be completed in July 2018. As of July 2018, before database lock and with several procedure forms still temporarily inserted, a preliminary number of 1204 patients have been enrolled, who underwent a total of 1453 procedures. The prospective EMIT-AF/VTE registry program will expand the knowledge of periprocedural management of patients with NVAF and VTE receiving edoxaban in clinical practice.

Topics: Administration, Oral; Aged; Atrial Fibrillation; Dose-Response Relationship, Drug; Europe; Factor Xa Inhibitors; Female; Humans; Incidence; Male; Middle Aged; Prospective Studies; Pyridines; Secondary Prevention; Stroke; Thiazoles

There is limited information about the use of antithrombotic therapies and outcomes of Latin American (LatAm) subjects with atrial fibrillation. The global ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial compared the efficacy and safety of edoxaban versus warfarin over a median follow-up of 2.8 years.. The authors aimed to compare adjusted outcomes in Latin America versus outside Latin America and to compare outcomes stratified by anticoagulant treatment and region.. The authors analyzed clinical characteristics and outcomes, adjusted for baseline characteristics, the Human Development Index, and randomized treatment of 2,661 LatAm versus 18,444 non-Latin American subjects (nLAS).. After multivariable adjustment, LatAm subjects with atrial fibrillation had higher rates of intracranial hemorrhage and death than nLAS. Outcomes with higher-dose edoxaban versus warfarin were at least as favorable in LatAm subjects as in nLAS, with an even greater reduction in hemorrhagic stroke seen in LatAm.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Double-Blind Method; Embolism; Factor Xa Inhibitors; Female; Hospitalization; Humans; Intracranial Hemorrhages; Latin America; Male; Myocardial Infarction; Pyridines; Stroke; Thiazoles; Warfarin

Oral anticoagulation prevents ischemic strokes in patients with atrial fibrillation (AF). Early detection of AF and subsequent initiation of oral anticoagulation help to prevent strokes in AF patients. Implanted cardiac pacemakers and defibrillators allow seamless detection of atrial high rate episodes (AHRE), but the best antithrombotic therapy in patients with AHRE is not known.. Stroke risk is higher in pacemaker patients with AHRE than in those without, but the available data also show that stroke risk in patients with AHRE is lower than in patients with AF. Furthermore, only a minority of patients with AHRE will develop AF, many strokes occur without a temporal relation to AHRE, and AHRE can reflect other arrhythmias than AF or artifacts. An adequately powered controlled trial of oral anticoagulation in patients with AHRE is needed.. The Non-vitamin K antagonist Oral anticoagulants in patients with Atrial High rate episodes (NOAH-AFNET 6 ) trial tests whether oral anticoagulation with edoxaban is superior to prevent the primary efficacy outcome of stroke or cardiovascular death compared with aspirin or no antithrombotic therapy based on evidence-based indications. The primary safety outcome will be major bleeding. NOAH-AFNET 6 will randomize 3,400 patients with AHRE, but without documented AF, aged ≥65 years with at least 1 other stroke risk factor, to oral anticoagulation therapy (edoxaban) or no anticoagulation. All patients will be followed until the end of this investigator-driven, prospective, parallel-group, randomized, event-driven, double-blind, multicenter phase IIIb trial. Patients will be censored when they develop AF and offered open-label anticoagulation. The sponsor is the Atrial Fibrillation NETwork (AFNET). The trial is supported by the DZHK (German Centre for Cardiovascular Research), the BMBF (German Ministry of Education and Research), and Daiichi Sankyo Europe.. NOAH-AFNET 6 will provide robust information on the effect of oral anticoagulation in patients with atrial high rate episodes detected by implanted devices.

Topics: Administration, Oral; Aged; Aspirin; Atrial Fibrillation; Disease-Free Survival; Double-Blind Method; Europe; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Follow-Up Studies; Heart Rate; Humans; Incidence; Male; Prospective Studies; Pyridines; Risk Factors; Stroke; Survival Rate; Thiazoles; Time Factors; Treatment Outcome; Vitamin K

The impact of different types of extracranial bleeding events on health-related quality of life and health-state utility among patients with atrial fibrillation is not well understood.. The ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) Trial compared edoxaban with warfarin with respect to the prevention of stroke or systemic embolism in atrial fibrillation. Data from the EuroQol-5D (EQ-5D-3L) questionnaire, prospectively collected at 3-month intervals for up to 48 months, were used to estimate the impact of different categories of bleeding events on health-state utility over 12 months following the event. Longitudinal mixed-effect models revealed that major gastrointestinal bleeds and major nongastrointestinal bleeds were associated with significant immediate decreases in utility scores (-0.029 [-0.044 to -0.014;. All categories of bleeding events were associated with negative impacts on health-state utility in patients with atrial fibrillation. Major bleeds were associated with relatively large immediate decreases in utility scores that gradually diminished over 12 months; clinically relevant nonmajor and minor bleeds were associated with smaller immediate decreases in utility that persisted over 12 months.. URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00781391.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Embolism; Factor Xa Inhibitors; Female; Gastrointestinal Hemorrhage; Health Status; Hemorrhage; Humans; Male; Middle Aged; Prospective Studies; Pyridines; Quality of Life; Risk Factors; Stroke; Surveys and Questionnaires; Thiazoles; Time Factors; Treatment Outcome; Warfarin

Edoxaban-a non-vitamin K antagonist oral anticoagulant (NOAC)- 60-mg and 30-mg once-daily dose regimens are noninferior versus well-managed warfarin for the prevention of stroke or systemic embolic events (SEE) with less major bleeding in patients with nonvalvular atrial fibrillation (NVAF). There are no published data from phase 3 clinical trials specifically evaluating the use of NOACs in elderly NVAF patients, especially those considered ineligible for available oral anticoagulants. The Edoxaban Low-Dose for EldeR CARE AF patients (ELDERCARE-AF) study is a phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter study that will compare the safety and efficacy of once-daily edoxaban 15 mg versus placebo in Japanese patients with NVAF ≥80 years of age who are considered ineligible for standard oral anticoagulant therapy. A total of 800 patients (400 in each treatment group) are planned for randomization (1:1) to either edoxaban or placebo using a stratified randomization method with CHADS

Topics: Administration, Oral; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dose-Response Relationship, Drug; Double-Blind Method; Factor Xa Inhibitors; Female; Humans; Incidence; Japan; Male; Pyridines; Stroke; Survival Rate; Thiazoles; Treatment Outcome; Warfarin

The choice between initiating a non-vitamin K antagonist oral anticoagulant (NOAC) and a vitamin K antagonist (VKA) in patients with atrial fibrillation (AF) may be challenging. To assist in this decision, we developed a risk score to identify patients for whom a therapeutic benefit of NOACs over VKA is predicted.. ENGAGE AF-TIMI 48 was a randomized clinical trial of edoxaban vs. warfarin in 21 105 patients with AF. Cox proportional hazard models identified factors associated with a serious net clinical outcome (NCO) of disabling stroke, life-threatening bleeding, and all-cause mortality in VKA naïve patients from the warfarin arm. These were used to develop an integer risk score. Performance was assessed by C-indices and validation by bootstrapping. Kaplan-Meier analyses were stratified by three score categories and treatment arm. Over a median of 2.7 years, 457 NCO events occurred in 2898 patients with a total person-time of 7549.5 years (6.05%/year). The risk prediction model (C = 0.693) for the NCO was translated into a 17-point integer score, with annualized event rates for the low, intermediate, and high-risk categories in the warfarin arm of 3.5%, 9.9%, and 20.8%, respectively. Therapeutic benefit of higher- and lower-dose edoxaban over warfarin was demonstrated in the high- and intermediate-risk, with equal benefit in the low-risk categories (P-interaction 0.008 and 0.014, respectively).. In VKA naive patients with AF, the TIMI-AF score can assist in the prediction of a poor composite outcome and guide selection of anticoagulant therapy by identifying a differential clinical benefit with a NOAC or VKA.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Double-Blind Method; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Pyridines; Risk Assessment; Risk Factors; Stroke; Thiazoles; Treatment Outcome; Warfarin

Whether the pattern of atrial fibrillation (AF) modifies the risk/benefit of anticoagulation is controversial. In ENGAGE AF-TIMI 48 trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48), the factor Xa inhibitor edoxaban was noninferior to warfarin in preventing stroke or systemic embolic events and significantly reduced bleeding and cardiovascular mortality. However, detailed analyses by AF pattern have not been reported.. The 21 105 patients were categorized as having paroxysmal (<7 days duration), persistent (≥7 days but <1 year), or permanent (≥1 year or failed cardioversion) AF patterns at randomization. Efficacy and safety outcomes were evaluated during the 2.8 years median follow-up and compared by AF pattern. The primary end point of stroke/systemic embolic event was lower in those patients with paroxysmal AF (1.49%/year), compared with persistent (1.83%/year; P-adj =0.015) and permanent AF (1.95%/year; P-adj =0.004). Overall, all-cause mortality also was lower with paroxysmal (3.0%/year) compared with persistent (4.4%/year; P-adj <0.001) and permanent AF (4.4%/year; P-adj <0.001). Annualized major bleeding rates were similar across AF patterns (2.86% versus 2.65% versus 2.73%). There was no effect modification by treatment assignment.. In ENGAGE AF-TIMI 48 trial, patients with paroxysmal AF suffered fewer thromboembolic events and deaths compared with those with persistent and permanent AF. The efficacy and safety profile of edoxaban as compared with warfarin was consistent across the 3 patterns of AF.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Pyridines; Risk Factors; Stroke; Thiazoles; Thromboembolism; Treatment Outcome; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Bioprosthesis; Blood Coagulation; Factor Xa Inhibitors; Heart Valve Prosthesis; Heart Valve Prosthesis Implantation; Hemorrhage; Humans; Pyridines; Risk Factors; Stroke; Thiazoles; Thromboembolism; Treatment Outcome; Warfarin

The use of non-vitamin K antagonist oral anticoagulants (NOACs) instead of vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and coexisting valvular heart disease (VHD) is of substantial interest.. This study explored outcomes in patients with AF with and without VHD in the ENGAGE AF-TIMI 48 (Effective Anticoagulation with factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial, comparing edoxaban with warfarin.. Valvular heart disease was defined as history or baseline echocardiography evidence of at least moderate aortic/mitral regurgitation, aortic stenosis, or prior valve surgery (bioprosthesis replacement, valve repair, valvuloplasty). Patients with moderate to severe mitral stenosis or mechanical heart valves were excluded from the trial. Comparisons were made of rates of stroke/systemic embolic event (SSEE), major bleeding, additional efficacy and safety outcomes, as well as net clinical outcomes, in patients with or without VHD treated with edoxaban or warfarin, using adjusted Cox proportional hazards.. After adjustment for multiple baseline characteristics, compared with no-VHD patients (n = 18,222), VHD patients (n = 2,824) had a similar rate of SSEE but higher rates of death (hazard ratio [HR]: 1.40; 95% confidence interval [CI]:1.26 to 1.56; p <0.001), major adverse cardiovascular events (HR: 1.29; 95% CI: 1.16 to 1.43; p <0.001), and major bleeding (HR: 1.21; 95% CI: 1.03 to 1.42; p = 0.02). Higher-dose edoxaban regimen had efficacy similar to warfarin in the presence of VHD (for SSEE, HR: 0.69; 95% CI: 0.44 to 1.07, in patients with VHD, and HR: 0.91; 95% CI: 0.77 to 1.07, in patients without VHD; p interaction [p. The presence of VHD increased the risk of death, major adverse cardiovascular events, and major bleeding but did not affect the relative efficacy or safety of higher-dose edoxaban versus warfarin in AF. (Global Study to Assess the Safety and Effectiveness of Edoxaban (DU-176b) vs. Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation [ENGAGE AF-TIMI 48]; NCT00781391).

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Double-Blind Method; Embolism; Female; Heart Valve Diseases; Hemorrhage; Humans; Male; Middle Aged; Pyridines; Stroke; Thiazoles; Warfarin

Edoxaban is a specific anti-Xa inhibitor that, in comparison to warfarin, has been found to be noninferior for the prevention of stroke or systemic embolism (SSE) and to reduce bleeding significantly in patients with nonvalvular atrial fibrillation (AF). The US Food and Drug Administration (FDA) approved the higher-dose edoxaban regimen (60/30 mg) in patients with AF and a creatinine clearance of ≤95 mL/min. We report for the first time the clinical characteristics, efficacy, and safety of the FDA-approved population in the ENGAGE AF--TIMI 48 trial.. The patients included had been treated with either warfarin or edoxaban 60/30 mg and had a creatinine clearance of ≤95 mL/min. The primary efficacy was SSE, and the principal safety end point was major bleeding (International Society on Thrombosis and Haemostasis classification). Median follow-up was 2.8 years.. Patients in the FDA-approved cohort were older, were more likely female, and had higher CHADS2 and HAS-BLED scores, as compared with patients not included in the FDA label. The primary end point occurred in 1.63%/y with edoxaban vs 2.02%/y with warfarin (hazard ratio [HR] 0.81, 95% CI 0.67-0.97, P = .023). Edoxaban significantly reduced the rate of hemorrhagic stroke (HR 0.47, 95% CI 0.31-0.72, P < .001) and cardiovascular death (HR 0.84, 95% CI 0.73-0.97, P = .015). Ischemic stroke rates were similar between the treatment groups (1.31%/y vs 1.39%/y, P = .97). Major bleeding was significantly lower with edoxaban (3.16%/y vs 3.77%/y; HR 0.84, 95% CI 0.72-0.98, P = .023).. In the FDA-approved cohort of the ENGAGE AF--TIMI 48 trial, treatment with edoxaban 60/30 mg was superior to warfarin in the prevention of SSE and significantly reduced cardiovascular death and bleeding, especially fatal bleeding and hemorrhagic stroke.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Dose-Response Relationship, Drug; Double-Blind Method; Drug Approval; Factor Xa; Factor Xa Inhibitors; Female; Humans; Male; Myocardial Infarction; Pyridines; Stroke; Thiazoles; Thrombolytic Therapy; United States; United States Food and Drug Administration; Warfarin

In the multinational, double-blind, double-dummy ENGAGE AF-TIMI 48 phase 3 study, once-daily edoxaban was non-inferior to warfarin for prevention of stroke or systemic embolism event (SEE) in patients with non-valvular atrial fibrillation (AF). Here, we evaluated the efficacy and safety of edoxaban in patients from East Asia.. Patients aged ≥21 years with documented AF and CHADS score ≥2 were randomized to receive once-daily edoxaban higher-dose (60 mg) or lower-dose (30 mg) regimen or warfarin dose-adjusted to an international normalized ratio of 2.0-3.0. Patients with a creatinine clearance of 30-50 ml/min, weighing ≤60 kg, or receiving strong p-glycoprotein inhibitors at randomization or during the study received a 50% dose reduction of edoxaban or matched placebo. This prespecified subanalysis included 1,943 patients from Japan, China, Taiwan, and South Korea. The annualized rate of stroke/SEE for higher-dose edoxaban was 1.34% vs. 2.62% for warfarin (hazard ratio [HR], 0.53; 95% confidence interval [CI]: 0.31-0.90, P=0.02) and 2.52% for lower-dose edoxaban (HR, 0.98; 95% CI: 0.63-1.54, P=0.93). Compared with warfarin (4.80%), major bleeding was significantly reduced for the higher-dose (2.86%; HR, 0.61; 95% CI: 0.41-0.89, P=0.011) and lower-dose regimens (1.59%; HR, 0.34; 95% CI: 0.21-0.54, P<0.001).. Once-daily edoxaban provided similar efficacy to warfarin while reducing major bleeding risk in the East Asian population.

Topics: Aged; Aged, 80 and over; Asia, Eastern; Atrial Fibrillation; Double-Blind Method; Embolism; Hemorrhage; Humans; Pyridines; Stroke; Thiazoles; Warfarin

We studied the concomitant use of single antiplatelet therapy (SAPT) on the efficacy and safety of the anti-Xa agent edoxaban in patients with atrial fibrillation (AF).. ENGAGE AF-TIMI 48 was a randomized trial that compared 2 dose regimens of edoxaban with warfarin. We studied both the approved high-dose edoxaban regimen (HDER; 60 mg daily reduced by one half in patients with anticipated increased drug exposure), as well as a lower-dose edoxaban regimen (LDER; 30 mg daily, also reduced by one half in patients with anticipated increased drug regimen). SAPT (aspirin in 92.5%) was administered at the discretion of the treating physician. Cox proportional hazard regressions stratified by SAPT at 3 months with treatment as a covariate were performed. The 4912 patients who received SAPT were more frequently male, with histories of coronary artery disease and diabetes, and had higher CHADS2Vasc and HAS BLED scores than did the 14 977 patients not receiving SAPT. When compared to patients not receiving SAPT, those receiving SAPT had a higher incidence of major bleeding; (adjusted hazard ratio [HRadj]=1.46; 95% CI, 1.27-1.67, P<0.001). SAPT did not alter the relative efficacy of edoxaban compared to warfarin in preventing stroke or systemic embolic events (SEEs): edoxaban versus warfarin without SAPT, hazard ratio (HRadj for HDER)=0.94; (95% CI: 0.77-1.15) with SAPT, HRadj=0.70 (95% CI: 0.50-0.98), P interaction (Pint)=0.14. (HRadj for LDER versus warfarin without SAPT=1.19 (95% CI 0.99-1.43) With SAPT, 1.03 (95% CI, 0.76-1.39) Pint=0.42. Major bleeding was lower with edoxaban than warfarin both without SAPT, HRadj for HDER=0.80 (95% CI, 0.68-0.95), and with SAPT, HRadj=0.82 (95% CI, 0.65-1.03; Pint=0.91). For LDER without SAPT (HRadj=0.56 [95% CI 0.46-0.67]) and with SAPT (HRadj=0.51 [95% CI 0.39-0.66]).. Patients with AF who were selected by their physicians to receive SAPT in addition to an anticoagulant had a similar risk of stroke/SEE and higher rates of bleeding than those not receiving SAPT. Edoxaban exhibited similar relative efficacy and reduced bleeding compared to warfarin, with or without concomitant SAPT.. URL: http://www.clinicaltrials.gov/. Unique identifier: NCT00781391.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Double-Blind Method; Drug Administration Schedule; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Pyridines; Risk Assessment; Risk Factors; Stroke; Thiazoles; Time Factors; Treatment Outcome; Warfarin

Topics: Aged; Anticoagulants; Atrial Fibrillation; Atrial Flutter; Combined Modality Therapy; Double-Blind Method; Electric Countershock; Factor Xa Inhibitors; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Pyridines; Risk Factors; Stroke; Thiazoles; Time Factors; Treatment Outcome; Warfarin

Elderly patients with atrial fibrillation are at higher risk of both ischemic and bleeding events compared to younger patients. In a prespecified analysis from the ENGAGE AF-TIMI 48 trial, we evaluate clinical outcomes with edoxaban versus warfarin according to age.. Twenty-one thousand one-hundred and five patients enrolled in the ENGAGE AF-TIMI 48 trial were stratified into 3 prespecified age groups: <65 (n=5497), 65 to 74 (n=7134), and ≥75 (n=8474) years. Older patients were more likely to be female, with lower body weight and reduced creatinine clearance, leading to higher rates of edoxaban dose reduction (10%, 18%, and 41% for the 3 age groups, P<0.001). Stroke or systemic embolic event (1.1%, 1.8%, and 2.3%) and major bleeding (1.8%, 3.3%, and 4.8%) rates with warfarin increased across age groups (Ptrend<0.001 for both). There were no interactions between age group and randomized treatment in the primary efficacy and safety outcomes. In the elderly (≥75 years), the rates of stroke/systemic embolic event were similar with edoxaban versus warfarin (hazard ratio 0.83 [0.66-1.04]), while major bleeding was significantly reduced with edoxaban (hazard ratio 0.83 [0.70-0.99]). The absolute risk difference in major bleeding (-82 events/10 000 pt-yrs) and in intracranial hemorrhage (-73 events/10 000 pt-yrs) both favored edoxaban over warfarin in older patients.. Age has a greater influence on major bleeding than thromboembolic risk in patients with atrial fibrillation. Given the higher rates of bleeding and death with increasing age, treatment of elderly patients with edoxaban provides an even greater absolute reduction in safety events over warfarin, compared to treatment with edoxaban versus warfarin in younger patients.. URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00781391.

Topics: Age Factors; Aged; Anticoagulants; Atrial Fibrillation; Double-Blind Method; Embolism; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Pyridines; Stroke; Thiazoles; Treatment Outcome; Warfarin

In the ENGAGE AF-TIMI 48 trial, edoxaban, a factor Xa inhibitor, was not found to be inferior to warfarin for the prevention of stroke or systemic embolic events (SEE) in patients with atrial fibrillation (AF) and was associated with significantly less bleeding. The higher-dose edoxaban regimen (HDER; 60 mg dose-reduced to 30 mg once daily) has been approved in various countries in Europe, the USA, and Japan. Among patients treated with vitamin K antagonists (VKAs), symptomatic heart failure (HF) is an independent risk factor for lower time-in-therapeutic range, which reduces the efficacy and safety of VKA therapy. We evaluated the efficacy and safety of edoxaban compared with warfarin across the spectrum of HF severity in the ENGAGE AF-TIMI 48 trial.. Of 14 071 patients randomized to well-controlled warfarin or the HDER, 5926 (42%) had no history of HF, 6344 (45%) were in New York Heart Association (NYHA) class I-II, and 1801 (13%) were in NYHA class III-IV. The efficacy of edoxaban compared with warfarin in preventing stroke/SEE was similar in patients without and with HF regardless of the severity of HF; [HDER vs. warfarin: No-HF: hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.69-1.11; NYHA class I-II: HR 0.88, 95% CI 0.69-1.12; NYHA class III-IV: HR 0.83, 95% CI 0.55-1.25; Pinteraction = 0.97]. Compared with warfarin, HDER was consistently associated with lower risk of major bleeding (No-HF: HR 0.82, 95% CI 0.68-0.99; NYHA class I-II: HR 0.79, 95% CI 0.65-0.96; NYHA class III-IV: HR 0.79, 95% CI 0.54-1.17; Pinteraction = 0.96).. The relative efficacy and safety of HDER compared with well-managed warfarin in AF patients with HF were similar to those without HF.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Double-Blind Method; Factor Xa Inhibitors; Female; Heart Failure; Hemorrhage; Humans; Male; Middle Aged; Proportional Hazards Models; Pyridines; Stroke; Thiazoles; Treatment Outcome; Warfarin

Patients with atrial fibrillation and previous ischemic stroke (IS)/transient ischemic attack (TIA) are at high risk of recurrent cerebrovascular events despite anticoagulation. In this prespecified subgroup analysis, we compared warfarin with edoxaban in patients with versus without previous IS/TIA.. ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a double-blind trial of 21 105 patients with atrial fibrillation randomized to warfarin (international normalized ratio, 2.0-3.0; median time-in-therapeutic range, 68.4%) versus once-daily edoxaban (higher-dose edoxaban regimen [HDER], 60/30 mg; lower-dose edoxaban regimen, 30/15 mg) with 2.8-year median follow-up. Primary end points included all stroke/systemic embolic events (efficacy) and major bleeding (safety). Because only HDER is approved, we focused on the comparison of HDER versus warfarin.. Of 5973 (28.3%) patients with previous IS/TIA, 67% had CHADS2 (congestive heart failure, hypertension, age, diabetes, prior stroke/transient ischemic attack) >3 and 36% were ≥75 years. Compared with 15 132 without previous IS/TIA, patients with previous IS/TIA were at higher risk of both thromboembolism and bleeding (stroke/systemic embolic events 2.83% versus 1.42% per year; P<0.001; major bleeding 3.03% versus 2.64% per year; P<0.001; intracranial hemorrhage, 0.70% versus 0.40% per year; P<0.001). Among patients with previous IS/TIA, annualized intracranial hemorrhage rates were lower with HDER than with warfarin (0.62% versus 1.09%; absolute risk difference, 47 [8-85] per 10 000 patient-years; hazard ratio, 0.57; 95% confidence interval, 0.36-0.92; P=0.02). No treatment subgroup interactions were found for primary efficacy (P=0.86) or for intracranial hemorrhage (P=0.28).. Patients with atrial fibrillation with previous IS/TIA are at high risk of recurrent thromboembolism and bleeding. HDER is at least as effective and is safer than warfarin, regardless of the presence or the absence of previous IS or TIA.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Double-Blind Method; Female; Humans; Male; Middle Aged; Pyridines; Recurrence; Secondary Prevention; Stroke; Thiazoles; Treatment Outcome; Warfarin

Edoxaban, an oral factor Xa inhibitor, is non-inferior for prevention of stroke and systemic embolism in patients with atrial fibrillation and is associated with less bleeding than well controlled warfarin therapy. Few safety data about edoxaban in patients undergoing electrical cardioversion are available.. We did a multicentre, prospective, randomised, open-label, blinded-endpoint evaluation trial in 19 countries with 239 sites comparing edoxaban 60 mg per day with enoxaparin-warfarin in patients undergoing electrical cardioversion of non-valvular atrial fibrillation. The dose of edoxaban was reduced to 30 mg per day if one or more factors (creatinine clearance 15-50 mL/min, low bodyweight [≤60 kg], or concomitant use of P-glycoprotein inhibitors) were present. Block randomisation (block size four)-stratified by cardioversion approach (transoesophageal echocardiography [TEE] or not), anticoagulant experience, selected edoxaban dose, and region-was done through a voice-web system. The primary efficacy endpoint was a composite of stroke, systemic embolic event, myocardial infarction, and cardiovascular mortality, analysed by intention to treat. The primary safety endpoint was major and clinically relevant non-major (CRNM) bleeding in patients who received at least one dose of study drug. Follow-up was 28 days on study drug after cardioversion plus 30 days to assess safety. This trial is registered with ClinicalTrials.gov, number NCT02072434.. Between March 25, 2014, and Oct 28, 2015, 2199 patients were enrolled and randomly assigned to receive edoxaban (n=1095) or enoxaparin-warfarin (n=1104). The mean age was 64 years (SD 10·54) and mean CHA. ENSURE-AF is the largest prospective randomised clinical trial of anticoagulation for cardioversion of patients with non-valvular atrial fibrillation. Rates of major and CRNM bleeding and thromboembolism were low in the two treatment groups.. Daiichi Sankyo provided financial support for the study.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Electric Countershock; Enoxaparin; Factor Xa Inhibitors; Hemorrhage; Humans; Middle Aged; Prospective Studies; Pyridines; Stroke; Thiazoles; Thromboembolism; Warfarin

Anticoagulation is often avoided in patients with atrial fibrillation who are at an increased risk of falling.. This study assessed the relative efficacy and safety of edoxaban versus warfarin in the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial in patients with atrial fibrillation judged to be at increased risk of falling.. We performed a pre-specified analysis of the ENGAGE AF-TIMI 48, comparing patients with versus without increased risk of falling.. Nine hundred patients (4.3%) were judged to be at increased risk of falling. These patients were older (median, 77 vs. 72 years; p < 0.001), and had a higher prevalence of comorbidities including prior stroke/transient ischemic attack, diabetes, and coronary artery disease. After multivariable adjustment, patients at increased risk of falling experienced more bone fractures caused by falling (adjusted hazard ratio [HRadj]: 1.88; 95% confidence interval [CI]: 1.49 to 2.38; p < 0.001), major bleeding (HRadj: 1.30; 95% CI: 1.04 to 1.64; p = 0.023), life-threatening bleeding (HRadj: 1.67; 95% CI: 1.11 to 2.50; p = 0.013), and all-cause death (HRadj: 1.45; 95% CI: 1.23 to 1.70; p < 0.001), but not ischemic events including stroke/systemic embolic event (HRadj: 1.16; 95% CI: 0.89 to 1.51; p = 0.27). No treatment interaction was observed between either dosing regimens of edoxaban and warfarin for the efficacy and safety outcomes. Treatment with edoxaban resulted in a greater absolute risk reduction in severe bleeding events and all-cause mortality compared with warfarin.. Edoxaban is an attractive alternative to warfarin in patients at increased risk of falling, because it is associated with an even greater absolute reduction in severe bleeding events and mortality. (Effective aNticaoGulation with factor xA next Generation in Atrial Fibrillation [ENGAGE AF-TIMI 48]; NCT00781391).

Topics: Accidental Falls; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Pyridines; Risk Factors; Single-Blind Method; Stroke; Thiazoles; Warfarin

Edoxaban is an oral, once-daily factor Xa inhibitor that is non-inferior to well-managed warfarin in patients with atrial fibrillation (AF) for the prevention of stroke and systemic embolic events (SEEs). We examined the efficacy and safety of edoxaban vs. warfarin in patients who were vitamin K antagonist (VKA) naive or experienced.. ENGAGE AF-TIMI 48 randomized 21 105 patients with AF at moderate-to-high risk of stroke to once-daily edoxaban vs. warfarin. Subjects were followed for a median of 2.8 years. The primary efficacy endpoint was stroke or SEE. As a pre-specified subgroup, we analysed outcomes for those with or without prior VKA experience (>60 consecutive days). Higher-dose edoxaban significantly reduced the risk of stroke or SEE in patients who were VKA naive [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.56-0.90] and was similar to warfarin in the VKA experienced (HR 1.01, 95% CI 0.82-1.24; P interaction = 0.028). Lower-dose edoxaban was similar to warfarin for stroke or SEE prevention in patients who were VKA naive (HR 0.92, 95% CI 0.73-1.15), but was inferior to warfarin in those who were VKA experienced (HR 1.31, 95% 1.08-1.60; P interaction = 0.019). Both higher-dose and lower-dose edoxaban regimens significantly reduced the risk of major bleeding regardless of prior VKA experience (P interaction = 0.90 and 0.71, respectively).. In patients with AF, edoxaban appeared to demonstrate greater efficacy compared with warfarin in patients who were VKA naive than VKA experienced. Edoxaban significantly reduced major bleeding compared with warfarin regardless of prior VKA exposure.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Double-Blind Method; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Pyridines; Risk Factors; Stroke; Thiazoles; Treatment Outcome; Warfarin

Warfarin is the most widely used oral anticoagulant worldwide, but serious bleeding complications are common. We tested whether genetic variants can identify patients who are at increased risk of bleeding with warfarin and, consequently, those who would derive a greater safety benefit with a direct oral anticoagulant rather than warfarin.. ENGAGE AF-TIMI 48 was a randomised, double-blind trial in which patients with atrial fibrillation were assigned to warfarin to achieve a target international normalised ratio of 2·0-3·0, or to higher-dose (60 mg) or lower-dose (30 mg) edoxaban once daily. A subgroup of patients was included in a prespecified genetic analysis and genotyped for variants in CYP2C9 and VKORC1. The results were used to create three genotype functional bins (normal, sensitive, and highly sensitive responders to warfarin). This trial is registered with ClinicalTrials.gov, number NCT00781391.. 14,348 patients were included in the genetic analysis. Of 4833 taking warfarin, 2982 (61·7%) were classified as normal responders, 1711 (35·4%) as sensitive responders, and 140 (2·9%) as highly sensitive responders. Compared with normal responders, sensitive and highly sensitive responders spent greater proportions of time over-anticoagulated in the first 90 days of treatment (median 2·2%, IQR 0-20·2; 8·4%, 0-25·8; and 18·3%, 0-32·6; ptrend<0·0001) and had increased risks of bleeding with warfarin (sensitive responders hazard ratio 1·31, 95% CI 1·05-1·64, p=0·0179; highly sensitive responders 2·66, 1·69-4·19, p<0·0001). Genotype added independent information beyond clinical risk scoring. During the first 90 days, when compared with warfarin, treatment with edoxaban reduced bleeding more so in sensitive and highly sensitive responders than in normal responders (higher-dose edoxaban pinteraction=0·0066; lower-dose edoxaban pinteraction=0·0036). After 90 days, the reduction in bleeding risk with edoxaban versus warfarin was similarly beneficial across genotypes.. CYP2C9 and VKORC1 genotypes identify patients who are more likely to experience early bleeding with warfarin and who derive a greater early safety benefit from edoxaban compared with warfarin.. Daiichi Sankyo.

Topics: Anticoagulants; Atrial Fibrillation; Cytochrome P-450 CYP2C9; Double-Blind Method; Factor Xa Inhibitors; Genetic Variation; Genotype; Hemorrhage; Humans; International Normalized Ratio; Pharmacogenetics; Pyridines; Risk Assessment; Stroke; Thiazoles; Vitamin K Epoxide Reductases; Warfarin

New oral anticoagulants for stroke prevention in atrial fibrillation were developed to be given in fixed doses without the need for the routine monitoring that has hindered usage and acceptance of vitamin K antagonists. A concern has emerged, however, that measurement of drug concentration or anticoagulant activity might be needed to prevent excess drug concentrations, which significantly increase bleeding risk. In the ENGAGE AF-TIMI 48 trial, higher-dose and lower-dose edoxaban were compared with warfarin in patients with atrial fibrillation. Each regimen incorporated a 50% dose reduction in patients with clinical features known to increase edoxaban drug exposure. We aim to assess whether adjustment of edoxaban dose in this trial prevented excess drug concentration and the risk of bleeding events.. We analysed data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. We correlated edoxaban dose, plasma concentration, and anti-Factor Xa (FXa) activity and compared efficacy and safety outcomes with warfarin stratified by dose reduction status. Patients with atrial fibrillation and at moderate to high risk of stroke were randomly assigned in a 1:1:1 ratio to receive warfarin, dose adjusted to an international normalised ratio of 2·0-3·0, higher-dose edoxaban (60 mg once daily), or lower-dose edoxaban (30 mg once daily). Randomisation was done with use of a central, 24 h, interactive, computerised response system. International normalised ratio was measured using an encrypted point-of-care device. To maintain masking, sham international normalised ratio values were generated for patients assigned to edoxaban. Edoxaban (or placebo-edoxaban in warfarin group) doses were halved at randomisation or during the trial if patients had creatinine clearance 30-50 mL/min, bodyweight 60 kg or less, or concomitant medication with potent P-glycoprotein interaction. Efficacy outcomes included the primary endpoint of all-cause stroke or systemic embolism, ischaemic stroke, and all-cause mortality. Safety outcomes included the primary safety endpoint of major bleeding, fatal bleeding, intracranial haemorrhage, and gastrointestinal bleeding. This trial is registered with ClinicalTrials.gov, number NCT00781391.. Between Nov 19, 2008 and Nov 22, 2010, 21 105 patients were recruited. Patients who met clinical criteria for dose reduction at randomisation (n=5356) had higher rates of stroke, bleeding, and death compared with those who did not have a dose reduction (n=15 749). Edoxaban dose ranged from 15 mg to 60 mg, resulting in a two-fold to three fold gradient of mean trough drug exposure (16·0-48·5 ng/mL in 6780 patients with data available) and mean trough anti-FXa activity (0·35-0·85 IU/mL in 2865 patients). Dose reduction decreased mean exposure by 29% (from 48·5 ng/mL [SD 45·8] to 34·6 ng/mL [30·9]) and 35% (from 24·5 ng/mL [22·7] to 16·0 ng/mL [14·5]) and mean anti-FXa activity by 25% (from 0·85 IU/mL [0·76] to 0·64 IU/mL [0·54]) and 20% (from 0·44 IU/mL [0·37] to 0·35 IU/mL [0·28]) in the higher-dose and lower-dose regimens, respectively. Despite the lower anti-FXa activity, dose reduction preserved the efficacy of edoxaban compared with warfarin (stroke or systemic embolic event: higher dose pinteraction=0·85, lower dose pinteraction=0·99) and provided even greater safety (major bleeding: higher dose pinteraction 0·02, lower dose pinteraction=0·002).. These findings validate the strategy that tailoring of the dose of edoxaban on the basis of clinical factors alone achieves the dual goal of preventing excess drug concentrations and helps to optimise an individual patient's risk of ischaemic and bleeding events and show that the therapeutic window for edoxaban is narrower for major bleeding than thromboembolism.. Daiichi-Sankyo Pharma Development.

Topics: Atrial Fibrillation; Double-Blind Method; Factor Xa Inhibitors; Hemorrhage; Humans; Pyridines; Stroke; Thiazoles; Treatment Outcome

We designed a prospective, randomized, open-label, blinded end point evaluation parallel group Phase 3b clinical trial comparing edoxaban (a new oral factor Xa inhibitor) with enoxaparin/warfarin followed by warfarin alone in subjects undergoing planned electrical cardioversion of non-valvular atrial fibrillation. The primary efficacy end point is the composite end points of stroke, systemic embolic event, myocardial infarction, and cardiovascular (CV) mortality, from randomization until the end of follow-up (day 56 post cardioversion). The primary safety end point is the composite of major and clinically-relevant non-major bleeding, from the first administration of study drug to end of treatment (Day 28 post cardioversion) +3 days. The primary efficacy analysis will be conducted on the intention-to-treat population whereas the primary safety analysis, on the safety population. The study includes stratification on the following levels: (i) approach to cardioversion (transoesophagel echocardiography or non-transoesophagel echocardiography) as determined by the Investigator; (ii) subject's experience in taking anticoagulants at the time of randomization (anticoagulant-experienced or anticoagulant-naïve); and (iii) assigned edoxaban dose (full 60 mg QD or reduced 30 mg dose QD). A subject with one or more factors (CrCl ≥15 mL/min and ≤50 mL/min, low body weight [≤60 kg], and concomitant use of p-pg inhibitors (excluding amiodarone) will receive a reduced dose (30 mg) of edoxaban if the subject is randomized to the edoxaban group. ENSURE-AF will be the largest prospective randomised trial of anticoagulation for cardioversion, also involving a Non-VKA Oral Anticoagulant-edoxaban.

Topics: Adult; Anticoagulants; Atrial Fibrillation; Cardiovascular Diseases; Electric Countershock; Factor Xa Inhibitors; Female; Humans; Male; Prospective Studies; Pyridines; Research Design; Stroke; Thiazoles; Thromboembolism; Warfarin

In the ENGAGE AF-TIMI 48 trial, the higher-dose edoxaban (HDE) regimen had a similar incidence of ischaemic stroke compared with warfarin, whereas a higher incidence was observed with the lower-dose regimen (LDE). Amiodarone increases edoxaban plasma levels via P-glycoprotein inhibition. The current pre-specified exploratory analysis was performed to determine the effect of amiodarone on the relative efficacy and safety profile of edoxaban.. At randomization, 2492 patients (11.8%) were receiving amiodarone. The primary efficacy endpoint of stroke or systemic embolic event was significantly lower with LDE compared with warfarin in amiodarone treated patients vs. patients not on amiodarone (hazard ratio [HR] 0.60, 95% confidence intervals [CIs] 0.36-0.99 and HR 1.20, 95% CI 1.03-1.40, respectively; P interaction <0.01). In patients randomized to HDE, no such interaction for efficacy was observed (HR 0.73, 95% CI 0.46-1.17 vs. HR 0.89, 95% CI 0.75-1.05, P interaction = 0.446). Major bleeding was similar in patients on LDE (HR 0.35, 95% CI 0.21-0.59 vs. HR 0.53, 95% CI 0.46-0.61, P interaction = 0.131) and HDE (HR 0.94, 95% CI 0.65-1.38 vs. HR 0.79, 95% CI 0.69-0.90, P interaction = 0.392) when compared with warfarin, independent of amiodarone use.. Patients randomized to the LDE treated with amiodarone at the time of randomization demonstrated a significant reduction in ischaemic events vs. warfarin when compared with those not on amiodarone, while preserving a favourable bleeding profile. In contrast, amiodarone had no effect on the relative efficacy and safety of HDE.

Topics: Aged; Amiodarone; Anti-Arrhythmia Agents; Anticoagulants; Atrial Fibrillation; Female; Hemorrhage; Humans; Male; Middle Aged; Pyridines; Stroke; Thiazoles; Treatment Outcome; Warfarin

In 21,105 patients with atrial fibrillation (AF), the ENGAGE AF-TIMI 48 trial demonstrated that both higher dose (60mg/30mg dose reduced) and lower dose (30mg/15mg dose reduced) once-daily regimens of edoxaban were non-inferior to warfarin for the prevention of stroke or systemic embolism (SE), with significantly lower rates of bleeding and cardiovascular death. Higher dose edoxaban was associated with a greater reduction in the risk of ischemic stroke than lower dose edoxaban, and the FDA approved higher dose edoxaban in patients with creatinine clearance ≤95mL/min. This study evaluated the economic value of higher dose edoxaban vs warfarin based on data from patients in ENGAGE within the FDA-approved population.. We assessed the cost-effectiveness of edoxaban vs warfarin over a lifetime horizon from the US healthcare system perspective using a Markov model based on a combination of ENGAGE AF-TIMI 48 trial data, US life tables, and published literature on the costs and long-term outcomes of non-fatal cardiovascular and bleeding events. Data from the ENGAGE AF-TIMI 48 trial were used to calculate age-adjusted event rates for warfarin and hazard ratios (HRs) for the relative impact of edoxaban on embolic and bleeding complications. Based on the wholesale acquisition price, edoxaban and warfarin were assumed to cost $9.24 and $0.36/day, respectively.. For edoxaban vs warfarin, lifetime incremental costs and QALYs were $16,384 and 0.444, respectively, yielding an incremental cost-effectiveness ratio (ICER) of $36,862/QALY gained, using data from patients with creatinine clearance ≤95mL/min in ENGAGE AF-TIMI 48. ICERs were more favorable for patients without compared to those with prior warfarin use; ICERs differed minimally by CHADS2 score.. Despite its higher acquisition cost, edoxaban is an economically attractive alternative to warfarin for the prevention of stroke and SE in patients with atrial fibrillation and creatinine clearance ≤95mL/min. These results were robust to variation of key model parameters, including assumptions regarding the cost and quality-of-life impact of stroke and bleeding events, and were favorable across both CHADS2 score stroke-risk categories.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Drug Monitoring; Embolism; Female; Hemorrhage; Humans; Male; Middle Aged; Patient Selection; Pyridines; Risk Assessment; Stroke; Survival Analysis; Thiazoles; Treatment Outcome; Warfarin

The once-daily oral factor Xa inhibitor, edoxaban, is as effective as warfarin in preventing stroke and systemic embolism while decreasing bleeding in a phase III trial of patients with atrial fibrillation at moderate-high stroke risk. Limited data regarding cerebrovascular events with edoxaban were reported previously.. We analyzed the subtypes of cerebrovascular events in 21 105 patients participating in Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) comparing outcomes among patients randomized to warfarin versus 2 edoxaban regimens (high dose, low dose). The primary end point for this prespecified analysis of cerebrovascular events was all stroke (ischemic plus hemorrhagic), defined as an abrupt onset of focal neurological deficit because of infarction or bleeding with symptoms lasting ≥24 hours or fatal in <24 hours. Independent stroke neurologists unaware of treatment adjudicated all cerebrovascular events.. Patients randomized to high-dose edoxaban had fewer strokes on-treatment (hazard ratio, 0.80; 95% confidence interval, 0.65-0.98) than warfarin (median time-in-therapeutic range, 68.4%); patients in the low-dose edoxaban group had similar rates (hazard ratio, 1.10 versus warfarin; 95% confidence interval, 0.91-1.32). Rates of ischemic stroke or transient ischemic attack were similar with high-dose edoxaban (1.76% per year) and warfarin (1.73% per year; P=0.81), but more frequent with low-dose edoxaban (2.48% per year; P<0.001). Both edoxaban regimens significantly reduced hemorrhagic stroke and other subtypes of intracranial bleeds.. In patients with atrial fibrillation, once-daily edoxaban was as effective as warfarin in preventing all strokes, with significant reductions in various subtypes of intracranial bleeding. Ischemic cerebrovascular event rates were similar with high-dose edoxaban and warfarin, whereas low-dose edoxaban was less effective than warfarin.. http://www.clinicaltrials.gov. Unique identifier: NCT00781391.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Pyridines; Stroke; Thiazoles; Treatment Outcome; Warfarin

Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known.. We conducted a randomized, double-blind, double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation (median follow-up, 2.8 years). The primary efficacy end point was stroke or systemic embolism. Each edoxaban regimen was tested for noninferiority to warfarin during the treatment period. The principal safety end point was major bleeding.. The annualized rate of the primary end point during treatment was 1.50% with warfarin (median time in the therapeutic range, 68.4%), as compared with 1.18% with high-dose edoxaban (hazard ratio, 0.79; 97.5% confidence interval [CI], 0.63 to 0.99; P<0.001 for noninferiority) and 1.61% with low-dose edoxaban (hazard ratio, 1.07; 97.5% CI, 0.87 to 1.31; P=0.005 for noninferiority). In the intention-to-treat analysis, there was a trend favoring high-dose edoxaban versus warfarin (hazard ratio, 0.87; 97.5% CI, 0.73 to 1.04; P=0.08) and an unfavorable trend with low-dose edoxaban versus warfarin (hazard ratio, 1.13; 97.5% CI, 0.96 to 1.34; P=0.10). The annualized rate of major bleeding was 3.43% with warfarin versus 2.75% with high-dose edoxaban (hazard ratio, 0.80; 95% CI, 0.71 to 0.91; P<0.001) and 1.61% with low-dose edoxaban (hazard ratio, 0.47; 95% CI, 0.41 to 0.55; P<0.001). The corresponding annualized rates of death from cardiovascular causes were 3.17% versus 2.74% (hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), and 2.71% (hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P=0.008), and the corresponding rates of the key secondary end point (a composite of stroke, systemic embolism, or death from cardiovascular causes) were 4.43% versus 3.85% (hazard ratio, 0.87; 95% CI, 0.78 to 0.96; P=0.005), and 4.23% (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.32).. Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes. (Funded by Daiichi Sankyo Pharma Development; ENGAGE AF-TIMI 48 ClinicalTrials.gov number, NCT00781391.).

Topics: Adult; Aged; Anticoagulants; Atrial Fibrillation; Cardiovascular Diseases; Double-Blind Method; Embolism; Female; Follow-Up Studies; Hemorrhage; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Pyridines; Stroke; Thiazoles; Warfarin

Edoxaban is a novel, orally available, highly specific direct inhibitor of factor Xa and is currently being developed for the treatment and prevention of venous thromboembolism and prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). The objectives of the present analyses were to characterise edoxaban population pharmacokinetics (PPK) and identify potential intrinsic and extrinsic factors affecting variability in edoxaban exposure, determine if there are relationships between edoxaban pharmacokinetics or biomarkers and the risk of bleeding in patients with NVAF using an exposure-response model, and to use the PPK and exposure-response model to support dose selection for a phase III trial of edoxaban in patients with NVAF. PPK analysis of data from 1,281 edoxaban-dosed subjects with intrinsic factors such as renal impairment or NVAF and extrinsic factors such as concomitant medications revealed significant effects of renal impairment and concomitant strong P-glycoprotein (P-gp) inhibitors on the pharmacokinetics of edoxaban. Exposure-response analysis found that in patients with NVAF, the incidence of bleeding events increased significantly with increasing edoxaban exposure, with steady-state minimum concentration (Cmin,ss) showing the strongest association. Clinical trial simulations of bleeding incidence were used to select 30 mg and 60 mg once-daily edoxaban with 50% dose reductions for patients with moderate renal impairment or receiving concomitant strong P-gp inhibitors as the treatment regimens in the ENGAGE AF-TIMI 48 (NCT00781391) trial.

Topics: Administration, Oral; Anticoagulants; ATP Binding Cassette Transporter, Subfamily B, Member 1; Atrial Fibrillation; Blood Coagulation; Clinical Trials, Phase III as Topic; Computer Simulation; Dose-Response Relationship, Drug; Drug Interactions; Factor Xa; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Kidney Diseases; Logistic Models; Male; Models, Biological; Models, Statistical; Pyridines; Research Design; Risk Assessment; Risk Factors; Stroke; Thiazoles; Treatment Outcome

The primary objective of this study was to compare the safety of four fixed-dose regimens of edoxaban with warfarin in patients with non-valvular atrial fibrillation (AF). In this 12-week, parallel-group, multicentre, multinational study, 1,146 patients with AF and risk of stroke were randomised to edoxaban 30 mg qd, 30 mg bid, 60 mg qd, or 60 mg bid or warfarin dose-adjusted to a target international normalised ratio of 2.0-3.0. The study was double-blind to edoxaban dose, but open-label to warfarin. Primary outcomes were occurrence of major and/or clinically relevant non-major bleeding and elevated hepatic enzymes and/or bilirubin. Mean age was 65 +/- 8.7 years and 64.4% were warfarin-naïve. Whereas major plus clinically relevant non-major bleeding occurred in 3.2% of patients randomised to warfarin, the incidence of bleeding was significantly higher with the edoxaban 60 mg bid (10.6%; p=0.002) and 30 mg bid regimens (7.8%; p=0.029), but not with the edoxaban 60 mg qd (3.8%) or 30 mg qd regimens (3.0%). For the same total daily dose of 60 mg, both bleeding frequency and trough edoxaban concentrations were higher in the 30-mg bid group than in the 60-mg qd group. There were no significant differences in hepatic enzyme elevations or bilirubin values among the groups. The safety profiles of edoxaban 30 and 60 mg qd in patients with AF were similar to warfarin. In contrast, the edoxaban bid regimens were associated with more bleeding than warfarin. These results suggest that in this three-month study, edoxaban 30 or 60 mg qd are safe and well-tolerated.

Topics: Administration, Oral; Aged; Alanine Transaminase; Anticoagulants; Aspartate Aminotransferases; Atrial Fibrillation; Bilirubin; Biomarkers; Blood Coagulation; Double-Blind Method; Europe, Eastern; Factor Xa; Factor Xa Inhibitors; Female; Fibrin Fibrinogen Degradation Products; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Pyridines; Stroke; Thiazoles; Time Factors; Treatment Outcome; United States; Warfarin

Vitamin K antagonists have been the standard oral antithrombotic used for more than a half century for prevention and treatment of thromboembolism. Their limitations include multiple food and drug interactions and need for frequent monitoring and dose adjustments. Edoxaban is a selective and direct factor Xa inhibitor that may provide effective, safe, and more convenient anticoagulation.. ENGAGE AF-TIMI 48 is a phase 3, randomized, double-blind, double-dummy, multinational, noninferiority design megatrial comparing 2 exposure strategies of edoxaban to warfarin. Approximately 20,500 subjects will be randomized to edoxaban high exposure (60 mg daily, adjusted for drug clearance), edoxaban low exposure (30 mg daily, adjusted for drug clearance), or warfarin titrated to an international normalized ratio of 2.0 to 3.0. The edoxaban strategies provide for dynamic dose reductions in subjects with anticipated increased drug exposure. Blinded treatment is maintained through the use of sham international normalized ratios in patients receiving edoxaban. Eligibility criteria include electrical documentation of atrial fibrillation ≤12 months and a CHADS(2) score ≥2. Randomization is stratified by CHADS(2) score and anticipated drug exposure. The primary objective is to determine whether edoxaban is noninferior to warfarin for the prevention of stroke and systemic embolism. The primary safety end point is modified International Society on Thrombosis and Haemostasis major bleeding. Recruitment began in November 2008. The expected median follow-up is 24 months.. ENGAGE AF-TIMI 48 is a phase 3 comparison of the novel oral factor Xa inhibitor edoxaban to warfarin for the prevention of thromboembolism in patients with atrial fibrillation.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Factor Xa Inhibitors; Female; Follow-Up Studies; Humans; Male; Middle Aged; Myocardial Infarction; Pyridines; Retrospective Studies; Stroke; Thiazoles; Thrombolytic Therapy; Treatment Outcome; Warfarin

Edoxaban is a non-vitamin K antagonist oral anticoagulant (NOAC) widely used for the long-term prevention of stroke in patients with non-valvular atrial fibrillation (NVAF). Adherence to NOAC therapy has been unsatisfactory and decreases over time. Remedial strategies are currently used to address the non-adherence events. Current recommendations, however, are generic and not well supported by evidence. The aim of this study was to explore appropriate remedial dosing regimens for non-adherent edoxaban-treated NVAF patients through Monte Carlo simulation.. Six regimens were compared with the current recommendations of the European Heart Rhythm Association (EHRA) guide based on total deviation time. Both edoxaban plasma concentration and intrinsic Factor Xa activity were considered. Monte Carlo simulations were performed using RxODE based on a published population pharmacokinetic/pharmacodynamic (PK/PD) model.. The proposed remedial strategies were different than the EHRA recommendations and were related to the delay time. However, it was found that the missed dose can be administered immediately if the delay time is within 11 h. When the delay is between 12 and 19 h, a half dose followed by a regular dosing schedule is recommended. When the delay time exceeds 19 h, a full dose followed by a half dose is preferred.. PK/PD modelling and simulation are effective in developing and evaluating the remedial strategies of edoxaban, which can help maximise its therapeutic effect.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Humans; Pyridines; Stroke

Recent data have suggested that insulin-requiring diabetes mostly contributes to the overall increase of thromboembolic risk in patients with atrial fibrillation (AF) on warfarin. We evaluated the prognostic role of a different diabetes status on clinical outcome in a large cohort of AF patients treated with edoxaban.. We accessed individual patients' data from the prospective, multicenter, ETNA-AF Europe Registry. We compared the rates of ischemic stroke/transient ischemic attack (TIA)/systemic embolism, myocardial infarction (MI), major bleeding and all-cause death at 2 years according to diabetes status.. Out of an overall population of 13,133 patients, 2885 had diabetes (22.0%), 605 of whom (21.0%) were on insulin. The yearly incidence of ischemic stroke/TIA/systemic embolism was 0.86% in patients without diabetes, 0.87% in diabetic patients not receiving insulin (p = 0.92 vs no diabetes) and 1.81% in those on insulin (p = 0.002 vs no diabetes; p = 0.014 vs diabetes not on insulin). The annual rates of MI and major bleeding were 0.40%, 0.43%, 1.04% and 0.90%, 1.10% and 1.71%, respectively. All-cause yearly mortality was 3.36%, 5.02% and 8.91%. At multivariate analysis, diabetes on insulin was associated with a higher rate of ischemic stroke/TIA/systemic embolism [adjusted HR 2.20, 95% CI 1.37-3.54, p = 0.0011 vs no diabetes + diabetes not on insulin] and all-cause death [aHR 2.13 (95% CI 1.68-2.68, p < 0.0001 vs no diabetes]. Diabetic patients not on insulin had a higher mortality [aHR 1.32 (1.11-1.57), p = 0.0015], but similar incidence of stroke/TIA/systemic embolism, MI and major bleeding, vs those without diabetes.. In a real-world cohort of AF patients on edoxaban, diabetes requiring insulin therapy, rather than the presence of diabetes per se, appears to be an independent factor affecting the occurrence of thromboembolic events during follow-up. Regardless of the diabetes type, diabetic patients had a lower survival compared with those without diabetes.

Topics: Anticoagulants; Atrial Fibrillation; Diabetes Mellitus; Embolism; Hemorrhage; Humans; Insulins; Ischemic Attack, Transient; Ischemic Stroke; Myocardial Infarction; Prospective Studies; Registries; Stroke; Thromboembolism

Data on non-vitamin K antagonist oral anticoagulants (NOACs) in transcatheter aortic valve replacement (TAVR) patients are controversial. In patients without atrial fibrillation (AF), rivaroxaban showed enhanced ischemia and bleeding as compared to standard of care. ENVISAGE showed enhanced bleeding in AF patients as compared to vitamin K antagonist (VKA). Only apixaban was non-inferior but failed superiority regarding bleeding in AF patients after TAVR. One could hypothesize that this might be due to pharmacokinetics of NOACs. Therefore, we compared outcome in rivaroxaban/edoxaban (once-daily) and apixaban (twice-daily) treated patients. 568 patients with indication for permanent oral anticoagulation due to AF undergoing TAVR were analyzed via inverse probability of treatment weighting. Valve academic research consortium complications during 30-day follow-up were assessed. Bleeding complications were similar in once-daily and twice-daily NOACs (major: 22 (7.5%) vs. 14 (5.3%), p = 0.285; minor: 66 (22.4%) vs. 46 (17.4%), p = 0.133). Complications did not change when splitting the cohort in the different agents apixaban, rivaroxaban and edoxaban. These findings remained robust after multivariate analysis. In summary, twice-daily and once-daily NOACs did not differ regarding bleeding complications in a hypothesis generating real-world cohort of TAVR patients with AF.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Fibrinolytic Agents; Hemorrhage; Humans; Rivaroxaban; Stroke; Transcatheter Aortic Valve Replacement; Treatment Outcome

Per-label dosing of direct oral anticoagulants (DOACs) is important for the prevention of stroke and systemic embolism among patients with non-valvular atrial fibrillation (NVAF), especially those with poor renal function, advanced age, low body weight or concomitant P-glycoprotein inhibitors. The study described DOAC use and dosing patterns in patients with NVAF in the UK.. Using Clinical Practice Research Datalink (CPRD Gold), patients' profiles were described at DOAC initiation (1 January 2016-31 March 2021) and followed for a mean [standard deviation (SD)] 2 (1) years. Patients were categorised as under-dosing: received a lower dose with no indication for a reduced dose; over-dosing: received a standard dose with an indication for a reduced dose; per-label dosing, according to Summary Product Characteristics (SmPC).. Forty thousand seven hundred forty-four adult patients with NVAF were identified (mean age: 75.3 (11.2) years; males: 55.4%); 22,827 (56.0%) initiated treatment with apixaban, 930 (2.3%) dabigatran, 5633 (13.8%) edoxaban and 11,354 (27.9%) rivaroxaban. Baseline Charlson comorbidity index ≥ 4 was 65.1%; CHA. Although most patients received per-label dosing, ~ one in five patients was incorrectly dosed with DOAC, which may lead to serious clinical consequences and increased healthcare burden.

Topics: Administration, Oral; Adult; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Humans; Male; Pyridones; Retrospective Studies; Rivaroxaban; Stroke

Topics: Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Humans; Pyridines; Stroke; Thiazoles

Four direct oral anticoagulants (DOACs) are used in Japan (edoxaban, rivaroxaban, apixaban, and dabigatran); however, few studies have examined the long-term treatment persistence of these DOACs. Furthermore, the factors associated with persistence remain unclear. This single-center, retrospective cohort study enrolled participants who were newly prescribed the 4 DOACs between January 1, 2012, and April 30, 2020. We assessed the treatment persistence rate by calculating the cumulative incidence rate of prescription switch or discontinuation for 5 years from the initial prescription. The factors associated with persistence were examined using multivariate analysis. The edoxaban was used as a reference for comparison with the other DOACs. The persistence rate at 5 years was 52.9% for all DOACs, including 67.0%, 51.6%, 50.2%, and 37.0% for edoxaban, rivaroxaban, apixaban, and dabigatran, respectively. Multivariate analysis revealed that age >65 years (hazard ratio [HR], 0.62 [95%CI, 0.41-0.93]), chronic kidney disease (HR, 1.63 [95%CI, 1.11-2.39]), baseline hemoglobin (HR, 0.85 [95%CI, 0.78-0.93]), diabetes mellitus (HR, 0.51 [95%CI, 0.29-0.93]), and type of DOACs (rivaroxaban: HR, 1.81 [95%CI, 1.03-3.18]; apixaban: HR, 2.00 [95%CI, 1.15-3.48]; and dabigatran: HR, 2.84 [95%CI, 1.66-4.86]) were significantly associated with nonpersistence at 1 year. At 5 years, diabetes mellitus (HR, 0.60 [95%CI, 0.37-0.97]) and type of DOAC were significantly associated with nonpersistence (rivaroxaban: HR, 1.79 [95%CI, 1.09-2.94]; apixaban: HR, 2.04 [95%CI, 1.26-3.31]; and dabigatran: HR, 2.76 [1.73-4.42]). Long-term treatment persistence differed according to the type of DOAC, with edoxaban exhibiting the highest level of persistence. The factors associated with persistence may change over the treatment course, but larger studies are required to generalize our findings.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Humans; Pyridones; Retrospective Studies; Rivaroxaban; Stroke

Direct oral anticoagulants (DOACs) have been increasingly utilised over warfarin. However, little is known about the relative consumption trends and costs of each DOAC at the global level.. An ecological study using pharmaceutical sales data from IQVIA-MIDAS database was used to estimate consumption and cost of individual DOACs in 65 countries from 2008 to 2019. Consumption was estimated from the volume of DOACs sold, expressed as defined-daily-dose/1000-inhabitants/day (DDDTID). Compound and absolute annual growth rates were reported to quantify consumption changes over time. Costs were estimated as manufacturer price per day-of-therapy.. Global consumption of dabigatran, rivaroxaban, apixaban and edoxaban were 0.31, 1.05, 1.08 and 0.78 DDDTID, respectively, in Q2-2019, compared to 0.23, 0.54, 0.21 and 0.03 in Q2-2015, with highest consumption in Western Europe, Northern Europe and Oceania (18.2, 14.07, 13.14 DDDTID). In most countries (46/65, 70%), rivaroxaban contributed to most DOAC consumption (35%-100%), whereas dabigatran accounted for less than one-third. Edoxaban accounted for < 20% of the total in Northern America and Europe but contributed significant proportions in Japan (28.58%) and South Korea (31.37%). Longer median time-to-adoption from FDA approval for apixaban and edoxaban was observed. Costs of all DOACs were ~2-4 times higher in the USA, Puerto Rico and Thailand than in other countries.. Regional differences exist in consumption pattern and trends of individual DOACs over the past decade. Consumption of rivaroxaban and apixaban overtook dabigatran in most countries, whereas use of edoxaban remains limited except in East Asian countries. The USA pays higher prices for DOACs than other countries.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Humans; Pyridones; Rivaroxaban; Stroke

Atrial fibrillation (AF) is associated with cognitive decline, with anticoagulated subjects potentially having a reduced risk compared with non-anticoagulated subjects. However, whether non-vitamin K antagonist oral anticoagulants (NOACs) may reduce the risk of dementia compared with vitamin K antagonists (VKAs) is unclear yet. Therefore, the risk of dementia was compared between AF subjects on NOACs versus VKAs.. AF subjects initiating anticoagulation between 2013 and 2019 were identified in Belgian nationwide data. Inverse probability of treatment weighted Cox regression was used to investigate cognitive outcomes.. Among 237,012 AF subjects (310,850 person-years (PYs)), NOAC use was associated with a significantly lower risk of dementia (adjusted hazard ratio (aHR) 0.91, 95% confidence interval (CI) (0.85-0.98)) compared with VKAs. A trend towards a lower risk of vascular dementia (aHR 0.89, 95% CI (0.76-1.04)) and significantly lower risk of other/unspecified dementia (aHR 0.91, 95% CI (0.84-0.99)) were observed with NOACs compared with VKAs, whereas the risk of Alzheimer's disease was similar (aHR 0.99, 95% CI (0.88-1.11)). Apixaban (aHR 0.91, 95% CI (0.83-0.99)) and edoxaban (aHR 0.79, 95% CI (0.63-0.99)) were associated with significantly lower risks of dementia compared with VKAs, while risks were not significantly different with dabigatran (aHR 1.02, 95% CI (0.93-1.12)) and rivaroxaban (aHR 0.97, 95% CI (0.90-1.05)). Comparable risks of dementia were observed between individual NOACs, except for significantly lower risks of dementia (aHR 0.93, 95% CI (0.87-0.98)) and other/unspecified dementia (aHR 0.90 (0.84-0.97)) with apixaban compared with rivaroxaban.. NOACs were associated with a significantly lower risk of dementia compared with VKAs, likely driven by apixaban and edoxaban use.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Belgium; Cohort Studies; Dabigatran; Dementia; Humans; Rivaroxaban; Stroke

Topics: Anticoagulants; Atrial Fibrillation; Cytochrome P-450 Enzyme System; Factor Xa Inhibitors; Humans; Pregnane X Receptor; Rivaroxaban; Stroke

Twice-daily dosing of non-vitamin K antagonist oral anticoagulants (NOACs) may reduce drug adherence compared with once-daily dosing of NOACs in patients with atrial fibrillation (AF), thus worsening clinical outcomes. We evaluated adherence to apixaban and dabigatran requiring twice-daily dosing compared with edoxaban or rivaroxaban with a once-daily dosing regimen and the subsequent clinical outcomes in patients with AF.. Adherence to each NOAC and outcomes were compared between patients who were diagnosed with AF and initiated NOACs between 2016 and 2017 using Korean claims data. High adherence was defined as the proportion of days covered (PDC) of the index NOAC ≥80%. The clinical outcomes included stroke, acute myocardial infarction, death, and composite outcome.. A total of 33,515 patients were analyzed (mean follow-up, 1.7 ± 1.3 years). The proportion of patients with high adherence to NOACs was 95%, which did not significantly differ according to the dosing regimen. The mean PDC for NOACs was as high as ~96%, which was the highest for apixaban users, intermediate for edoxaban or rivaroxaban users, and lowest for dabigatran users, regardless of the dosing regimen. Adverse outcomes in low adherence patients for each NOAC were higher than that of high adherence patients, regardless of the dosing frequency.. Adherence between once- and twice-daily dosing NOACs in patients with AF was high and similar among both dosing regimens. Patients with low NOAC adherence had poorer clinical outcomes, regardless of the dosing frequency.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Humans; Pyridones; Rivaroxaban; Stroke

Although widely used in clinical fields, real-world data on the role of warfarin and non-vitamin K oral anticoagulants (NOACs) for the secondary prevention of thromboembolic complications in ischemic stroke patients with nonvalvular atrial fibrillation (NVAF) are scarce.. This retrospective cohort study compared the effectiveness and safety of secondary prevention of NOAC and warfarin in ischemic stroke patients with NVAF.. From the Korean National Health Insurance Service Database, we included 16,762 oral anticoagulants-naive acute ischemic stroke patients with NVAF between July 2016 and June 2019. The main outcomes included ischemic stroke, systemic embolism, major bleeding, and all-cause of death.. In total, 1717 warfarin and 15,025 NOAC users were included in the analysis. After 1:8 propensity score matching, during the observation period, all types of NOACs had a significantly lower risk of ischemic stroke and systemic embolism than warfarin (edoxaban: adjusted hazard ratio [aHR], 0.80; 95% confidence interval [CI], 0.68-0.93, rivaroxaban: aHR, 0.82; 95% CI, 0.70-0.96, apixaban: aHR, 0.79; 95% CI, 0.69-0.91, and dabigatran: aHR, 0.82; 95% CI, 0.69-0.97). Edoxaban (aHR, 0.77; 95% CI, 0.62-0.96), apixaban (aHR, 0.73; 95% CI, 0.60-0.90), and dabigatran (aHR, 0.66; 95% CI, 0.51-0.86) had lower risks of major bleeding and all-cause of death.. All NOACs were more effective than warfarin in the secondary prevention of thromboembolic complications in ischemic stroke patients with NVAF. Except for rivaroxaban, most NOACs demonstrated a lower risk of major bleeding and all-cause of death than warfarin.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Embolism; Hemorrhage; Humans; Ischemic Stroke; Retrospective Studies; Rivaroxaban; Secondary Prevention; Stroke; Thromboembolism; Vitamin K; Warfarin

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Humans; Obesity; Prospective Studies; Registries; Stroke; Treatment Outcome

Diabetes represents a pro-thrombotic condition.. The primary objective was to evaluate the effects of Vitamin K Antagonist (VKA) compared to direct oral anticoagulants (DOACs) in diabetic and nondiabetic patients with non-valvular atrial fibrillation, newly diagnosed. The secondary objective was to evaluate the effects on the risk of bleeding.. We enrolled 300 patients with newly diagnosed atrial fibrillation. One hundred and sixteen patients were taking warfarin, 31 acenocumarol, 22 dabigatran, 80 rivaroxaban, 34 apixaban, and 17 edoxaban. We evaluated: anthropometric parameters, glycated hemoglobin (HbA. We did not record any differences among nondiabetic patients between VKA and DOACs. However, when we considered diabetic patients, we found a slight, but significant improvement of triglycerides and SD-LDL. As regards incidence of bleeding, minor bleeding was more frequent in VKA diabetic group compared to DOACs diabetic group; furthermore, the incidence of major bleeding was higher with VKA in nondiabetic and diabetic group, compared to patients with DOACs. Among DOACs, we recorded a higher incidence of bleeding (minor and major) with dabigatran compared to rivaroxaban, apixaban and edoxaban in nondiabetic and diabetic patients.. DOACs seem to be metabolically favourable in diabetic patients. Regarding incidence of bleeding, DOACs with the exception of dabigatran, seem better than VKA in diabetic patients.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Diabetes Mellitus; Hemorrhage; Humans; Rivaroxaban; Stroke

Direct oral anticoagulants (DOACs) represent the cornerstone therapy for cardioembolic events prevention in patients with nonvalvular atrial fibrillation (NVAF). In practice, the choice of one DOAC over another is guided by the decision-making process of the physician, which considers specific patient and drug characteristics. This study aimed to evaluate the clinical features and long-term outcomes of a real-world population treated with DOACs, where the use of the 4 different DOACs is quite equal. We conducted a retrospective observational, single-center, multidisciplinary study enrolling consecutive NVAF patients treated with one of the 4 DOACs. From an initial number of 753 patients, we excluded 72 patients because of loss to follow-up, at the end we enrolled 681:174 (23%) treated with dabigatran, 175 (23%) with apixaban, 190 (25%) with rivaroxaban, and 214 (29%) with edoxaban. Patients treated with apixaban were significantly older, more women represented (p <0.001), and with a higher cardioembolic and bleeding risk (p <0.001). Dabigatran was preferred in patients with liver failure (p = 0.008), whereas Apixaban and Edoxaban were chosen in chronic kidney disease (p = 0.002). At 3-year follow-up, 20 patients (2.7%) experienced a systemic thromboembolic event without significant differences in the 4 DOACs. In the same period, an International Society of Thrombosis and Hemostasis classification major bleeding event occurred in 26 patients (3.6%), more statistically correlated to edoxaban (6.1%) (p = 0.038). Thromboembolic events or major bleeding were higher in the edoxaban group (10%) compared with the others (p = 0.014). In our single-center real-world experience, the choice of the DOAC for a patient with NVAF was tailored to specific clinical features and drug pharmacokinetics of the patient. As a result, a small number of adverse events were observed.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Hemorrhage; Humans; Male; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Thromboembolism

A high risk of gastrointestinal bleeding has been reported with the use of some direct oral anticoagulants (DOACs). This risk may be of particular concern in individuals with associated anaemia. The aim of this study is to investigate potential differences in the risks of gastrointestinal bleeding and stroke among the four available DOACs in patients with atrial fibrillation (AF) and moderate or severe anaemia.. All Danish patients diagnosed with incident AF who had a baseline haemoglobin measurement and subsequently initiated DOAC therapy between 2012 and 2021 were identified through administrative registries. Only patients with moderate or severe anaemia (N = 7269) were included and evaluated regarding the risk of hospitalization for gastrointestinal bleeding and stroke. Standardized absolute 1-year risks of stroke and gastrointestinal bleeding were calculated from multivariable Cox regression analyses. DOACs were compared pairwise RESULTS: Compared with apixaban, both dabigatran and rivaroxaban were associated with a significantly increased risk of gastrointestinal bleeding with standardized 1-year risk ratios of 1.73 (95 % confidence interval [CI], 1.10-2.35) and 1.56 (95 % CI, 1.18-1.93), respectively, while no significant difference was seen in the comparison of apixaban with edoxaban 1.32 (95 % CI, 0.41-2.32). No significant differences in gastrointestinal bleeding were observed with pairwise comparisons of dabigatran, rivaroxaban and edoxaban. Finally, no significant difference in stroke risk among the four DOACs was observed.. In AF patients with moderate or severe anaemia, apixaban was associated with a significantly lower risk of gastrointestinal bleeding than dabigatran and rivaroxaban. No significant difference in stroke risk was observed across all four available DOACs.

Topics: Administration, Oral; Anemia; Anticoagulants; Atrial Fibrillation; Dabigatran; Gastrointestinal Hemorrhage; Humans; Pyridones; Rivaroxaban; Stroke

An increased risk of recurrent stroke is noted in patients with atrial fibrillation despite direct oral anticoagulant (DOAC) use. We investigated the efficacy and safety of treatment with each of 4 different DOACs or warfarin after DOAC failure.. We retrospectively analyzed patients with atrial fibrillation with ischemic stroke despite DOAC treatment between January 2002 and December 2016. The different outcomes of patients with DOAC failure were compared, including recurrent ischemic stroke, major cardiovascular events, intracranial hemorrhage and subarachnoid hemorrhage, mortality, and net composite outcomes according to switching to different DOACs or vitamin K antagonist after index ischemic stroke. We identified 3759 patients with DOAC failure. A total of 84 patients experienced recurrent ischemic stroke after switching to different oral anticoagulants, with a total follow-up time of 14 years. Using the vitamin K antagonist group as a reference, switching to any of the 4 DOACs was associated with a 69% to 77% reduced risk of major cardiovascular events (adjusted hazard ratio [aHR], 0.25 [95% CI, 0.16-0.39] for apixaban, 0.23 [95% CI, 0.14-0.37] for dabigatran, 0.23 [95% CI, 0.09-0.60] for edoxaban, and 0.31 [95% CI, 0.21-0.45] for rivaroxaban), and a 69% to 83% reduced risk of net composite outcomes (aHR, 0.25 [95% CI, 0.18-0.35] for apixaban, 0.17 [95% CI, 0.11-0.25] for dabigatran, 0.31 [95% CI, 0.17-0.56] for edoxaban, and 0.31 [95% CI, 0.23-0.41] for rivaroxaban).. In Asian patients with DOAC failure, continuing DOACs after index stroke was associated with fewer undesirable outcomes than switching to a vitamin K antagonist. Alternative pharmacologic and nonpharmacologic strategies warrant investigation.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Humans; Ischemic Stroke; Retrospective Studies; Rivaroxaban; Stroke; Subarachnoid Hemorrhage; Vitamin K; Warfarin

The aim of the study was to compare the real-world effectiveness and safety in atrial fibrillation (AF) patients treated with edoxaban versus other oral anticoagulants (OACs) (apixaban, dabigatran, rivaroxaban, and vitamin K antagonists [VKA]) in Germany.. Using a representative database of 3.5 million statutory health-insured lives in Germany, a retrospective cohort study was conducted to examine ischemic stroke (IS) or systemic embolism (SE) and major bleeding in AF patients initiating anticoagulant therapy from January 2014 through June 2017. Inverse probability of treatment weighting using propensity score was applied for baseline covariate adjustment. Cox proportional hazards models were used to estimate the adjusted risk (hazard ratio [HR]) of each outcome comparing edoxaban versus other OACs. Among 21,038 patients treated with OACs, 1236 edoxaban, 6053 apixaban, 1306 dabigatran, 7013 rivaroxaban, and 5430 VKA patients were included. The adjusted combined risks of IS or SE were lower (p < 0.05) for each edoxaban pairwise comparison with other OACs (HR: 0.83 vs. apixaban, 0.60 vs. dabigatran, 0.72 vs. rivaroxaban, 0.64 vs. VKA). Edoxaban favored lower risks of major bleeding compared with rivaroxaban (HR: 0.74) and VKA (HR: 0.47). No differences in the risk of major bleeding were found between edoxaban and apixaban (p = 0.33), and between edoxaban and dabigatran (p = 0.06).. Edoxaban was associated with better effectiveness compared with other OACs in AF patients from Germany. Edoxaban also demonstrated a favorable safety profile.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Cohort Studies; Dabigatran; Humans; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Thiazoles; Vitamin K

The three direct oral anticoagulants (DOAC), rivaroxaban, apixaban and dabigatran have been associated with lower risks of fractures compared to warfarin. However, no large scale studies have explored the associations with the newest DOAC, edoxaban, with fracture risk. The present study aims to elucidate the effects of edoxaban on the risk of hip fracture amongst elderly patients by comparing the incidence of new onset hip fracture between edoxaban and warfarin users in a Chinese population.. This was a retrospective population-based cohort study of patients with edoxaban or warfarin use between January 1st, 2016 and December 31st, 2019 in Hong Kong, China. Patients with less than one-month exposure, medication switching between warfarin and edoxaban, those who died within 30 days after drug exposure, prior human immunodeficiency virus infection, age <50 years old, and those with prior hip fractures were excluded. Propensity score matching (1:2) between edoxaban and warfarin users using the nearest neighbour method was performed based on demographics, prior comorbidities, and use of different medications. The study outcomes were new onset hip fractures, medically attended falls and all-cause mortality.. A total of 5014 patients including 579 edoxaban users and 4435 warfarin users (median age: 70 years old [interquartile range (IQR): 62-79], 56.66% males) with a median follow-up of 637.5 (IQR: 320-1073) days were included. In the matched cohort, edoxaban users had significantly lower rates of new onset hip fractures, medically attended falls and all-cause mortality. The protective value of edoxaban use against new onset hip fracture (hazard ratio [HR]: 0.13, 95% confidence interval [CI]: [0.03-0.54], p = 0.0051), medically attended falls (HR: 0.47, [0.29-0.75], p = 0.0018) and all-cause mortality (HR: 0.61, [0.42-0.87], p = 0.0059) in comparison to warfarin use persisted after matching. The significant relationship between edoxaban use and lower fracture risk was preserved in all sensitivity analyses using different approaches using the propensity score.. Edoxaban use is associated with lower risks of new onset hip fractures, medically attended falls and mortality risks compared to warfarin after propensity score matching.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Cohort Studies; Female; Hip Fractures; Humans; Male; Middle Aged; Propensity Score; Pyridines; Retrospective Studies; Risk Assessment; Stroke; Thiazoles; Warfarin

D-dimer levels can predict ischemic stroke in patients with acute heart failure (AHF). However, the effects of direct oral anticoagulants on D-dimer levels have not been investigated during admission for AHF in patients with atrial fibrillation (AF). This study examined D-dimer levels immediately after admission and following edoxaban initiation as a sub-analysis of a multi-center study that investigated the pharmacokinetics and pharmacodynamics of edoxaban in patients with nonvalvular AF (NVAF) and AHF.. Hospitalized patients with NVAF and AHF received edoxaban according to the label. The primary measure was the change in D-dimer levels on 7 consecutive days after admission for AHF. We also investigated differences according to prior edoxaban use (de novo at the time of admission or continuation).. In 10/13 (76.9%) de novo patients, D-dimer levels exceeded the reference value (1.0 µg/mL) at admission (mean, 2.12 µg/mL) and subsequently decreased in 9 patients (at final blood sampling: mean, 1.12 µg/mL); 1 patient did not fall below the reference value due to stasis dermatitis. In the continuation group, most patients had D-dimer levels below the reference value from Day 1 (mean, 0.93 µg/mL), and levels remained stable or decreased (at final blood sampling: mean, 0.49 µg/mL). No events of stroke were observed.. D-dimer levels may be elevated in patients with NVAF and AHF, particularly in those without prior anticoagulant treatment. Edoxaban may be effective for lowering and keeping D-dimer levels, a biomarker for predicting ischemic stroke, below the reference value in patients with NVAF and AHF.

Topics: Anticoagulants; Atrial Fibrillation; Fibrin Fibrinogen Degradation Products; Heart Failure; Humans; Ischemic Stroke; Pyridines; Stroke; Thiazoles

Anticoagulants are the standard therapy for patients with atrial fibrillation (AF) and antiplatelet therapy for those with coronary artery disease (CAD). However, compelling clinical evidence is still lacking regarding the long-term maintenance strategy with the combination of anticoagulant and antiplatelet drugs in patients with AF and stable CAD.. The EPIC-CAD trial is an investigator-initiated, multicenter, open-label randomized trial comparing the safety and efficacy of 2 antithrombotic strategies in patients with high-risk AF (CHA. As of December 2021, approximately 901 patients had been randomly enrolled over 2 years at 18 major cardiac centers across South Korea. The completed enrollment is expected at the mid-term of 2022, and the primary results will be available by 2023.. EPIC-CAD is a large-scale, multicenter, pragmatic design trial, which will provide valuable clinical insight into edoxaban-based long-term antithrombotic therapy in patients with high-risk AF and stable CAD.

Topics: Anticoagulants; Atrial Fibrillation; Coronary Artery Disease; Fibrinolytic Agents; Humans; Platelet Aggregation Inhibitors; Pyridines; Stroke; Thiazoles; Treatment Outcome

Safety and effectiveness of edoxaban was demonstrated in phase III, Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE-AF-TIMI 48) trial and is being confirmed in the post-authorization Edoxaban Treatment in routiNe clinical prActice for patients with Atrial Fibrillation in Europe (ETNA-AF-Europe) study in patients with atrial fibrillation. However, any post-authoriza tion safety study focusing on the safety of edoxaban treatment in Turkey with a prospective design has not been performed yet. The Evaluation of Treatment Safety in Patients with Atrial Fibrillation on Edoxaban Therapy in Real-Life in Turkey (ETAF-TR) study is designed to evaluate the safety and effectiveness of edoxaban treatment in atrial fibrillation in routine practice. The present article describes the design and rationale for the ETAF-TR Study.. The ETAF-TR (NCT04594915) is a national, multicenter, prospective, observational study that enrolled 858 patients from 32 centers. The primary outcome of the ETAF-TR study is any overt bleeding (consisting of major bleeding or clinically relevant nonmajor bleeding or any bleeding that does not meet this definition but is considered as overt bleeding by the par ticipating physician). Effectiveness, treatment persistence, and posology will also be evaluated in an explorative manner. The overall duration of follow-up will be 1 year; the first patient was enrolled in August 2020.. Results of ETAF-TR will add data from clinical practice to those from ENGAGE-AF trial and also ETNA-AF study. Comparing their results will enable to test the external validity of ENGAGE-AF trial in the country conditions.

Topics: Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Humans; Prospective Studies; Pyridines; Stroke; Thiazoles; Treatment Outcome; Turkey

Frailty is common in patients with atrial fibrillation (AF), with possible impact on therapies and outcomes. However, definitions of frailty are variable, and may not overlap with frailty perception among physicians. We evaluated the prevalence of frailty as perceived by enrolling physicians in the Edoxaban Treatment in Routine Clinical Practice for Patients With Non-Valvular AF (ETNA-AF)-Europe registry (NCT02944019), and compared it with an objective frailty assessment.. ETNA-AF-Europe is a prospective, multi-centre, post-authorization, observational study. There we assessed the presence of frailty according to (i) a binary subjective investigators' judgement and (ii) an objective measure, the Modified Frailty Index. Baseline data on frailty were available in 13 621/13 980 patients. Prevalence of perceived frailty was 10.6%, with high variability among participating countries and healthcare settings (range 5.9-19.6%). Conversely, only 5.0% of patients had objective frailty, with minimal variability (range 4.5-6.7%); and only <1% of patients were identified as frail by both approaches. Compared with non-frailty-perceived, perceived frail patients were older, more frequently female, and with lower body weight; conversely, objectively frail patients had more comorbidities. Non-recommended edoxaban dose regimens were more frequently prescribed in both frail patient categories.. Physicians' perception of frailty in AF patients is variable, mainly driven by age, sex, and weight, and quite different compared with the results of an objective frailty assessment. Whatever the approach, frailty appears to be associated with non-recommended anticoagulant dosages. Whether this apparent inappropriateness influences hard outcomes remains to be assessed.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Europe; Female; Frailty; Humans; Prospective Studies; Pyridines; Stroke; Thiazoles

Edoxaban is a non-vitamin K dependent oral anticoagulant (NOAC) licensed for stroke prevention in atrial fibrillation (SPAF). Outcome data on clinical effectiveness and safety in routine care are increasing.. In the prospective, non-interventional DRESDEN NOAC REGISTRY a network of 230 physicians enrolled >5000 NOAC patients who received prospective central follow. All reported outcome events (stroke/transient ischemic attack/systemic embolism; ISTH bleeding; death) were adjudicated using standard definitions.. Between 2016 and 2021, 1258 SPAF patients receiving edoxaban were followed for 927.1 ± 562.2 days with a mean edoxaban exposure of 790.3 ± 577.2 days. Edoxaban was discontinued by 274 patients (10.1/100 patient-years; 95% CI 8.9-11.3). The combined endpoint of stroke/TIA/systemic embolism occurred at a rate of 1.7/100 patient-years (95% CI 1.3-2.3) in the intention-to-treat analysis and at 1.3/100 patient-years (95% CI 0.9-1.9) in the on-treatment analysis (censored 3 days after last edoxaban intake). On-treatment rates of ISTH major bleeding were comparable for patients receiving edoxaban 30 mg OD (3.6/100 patient-years; 95% CI 2.2-5.5) or 60 mg OD (2.5/100 patient-years; 95% CI 1.8-3.2). A total of 151 patients (12.0%) died (4.7/100 patient-years; 95% CI 4.0-5.5), with non-stroke cardiovascular events (n = 50), infection/sepsis (n = 40) and terminal malignant disease (n = 31) being the leading causes of death.. Overall rates of effectiveness and safety outcomes were in line with latest real-world data (such as ETNA-AF registry) and confirm findings of the phase-III ENGAGE-AF trial. Non-thrombotic cardiovascular events and infectious diseases were the leading causes of death, whereas fatal stroke and fatal bleeding were rare.

Topics: Atrial Fibrillation; Embolism; Factor Xa Inhibitors; Hemorrhage; Humans; Ischemic Attack, Transient; Prospective Studies; Pyridines; Registries; Stroke; Thiazoles; Treatment Outcome

Patients with atrial fibrillation (AF) treated with oral anticoagulation still suffer from cardiovascular complications including cardiovascular death, stroke, and major bleeding. To identify risk factors for predicting stroke and bleeding outcomes in anticoagulated patients, we assessed 2-year outcomes in patients with AF treated with edoxaban in routine care. We also report the age-adjusted risk predictors of clinical outcomes.. The Edoxaban Treatment in Routine Clinical Practice for Patients With Non-Valvular Atrial Fibrillation (ETNA-AF) Europe (NCT02944019) is a prospective, multi-centre, post-authorisation, observational study with an overall 4-year follow-up conducted in 825 centres enrolling edoxaban-treated patients in 10 European countries. Of the 13 133 patients with AF (mean age: 73.6 ± 9.5 years), 5682 (43.3%) were female. At the 2-year follow-up, 9017/13 133 patients were still on edoxaban; 1830 discontinued treatment including 937 who died (annualised event rate of all-cause death was 3.87%). 518 (2.14%) patients died of cardiovascular causes; 234 (0.97%) experienced major bleeding and 168 (0.70%) experienced stroke or systemic embolic events (SEE). Intracranial haemorrhage was noted in 49 patients (0.20%). History of transient ischaemic attack (TIA) at baseline was the strongest predictor of ischaemic stroke or SEE (Wald χ2: 73.63; P < 0.0001). Low kidney function at baseline was the strongest predictor of major bleeding (Wald χ2: 30.68; P < 0.0001). History of heart failure (HF) was the strongest predictor of all-cause (Wald χ2: 146.99; P < 0.0001) and cardiovascular death (Wald χ2: 100.38; P < 0.0001).. Patients treated with edoxaban in ETNA-AF-Europe reported low 2-year event rates in unselected AF patients. Prior stroke, reduced kidney function, and HF identify patients at high risk of stroke, bleeding and all-cause/cardiovascular death, respectively.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Embolism; Factor Xa Inhibitors; Female; Heart Failure; Hemorrhage; Humans; Male; Middle Aged; Prospective Studies; Stroke; Treatment Outcome

The effectiveness and safety of edoxaban 60 mg and 30 mg for stroke prevention compared with warfarin in patients with atrial fibrillation have not been well-described in a nationwide cohort of Caucasian patients treated in standard clinical practice.. We used Danish nationwide registries to identify patients with atrial fibrillation during June 2016 and November 2018 who were treated with edoxaban or warfarin and computed rates per 100 person-years of thromboembolic, all-cause mortality, and bleeding events using an inverse probability of treatment weighting approach to account for baseline confounding. We used weighted pooled logistic regression to compute hazard ratios with 95% confidence intervals comparing events between edoxaban 60 mg and warfarin users; edoxaban 30 mg was not included in formal comparisons.. We identified 6451 atrial fibrillation patients, mean age was 72 years and 40% were females. A total of 1772 patients were treated with edoxaban 60 mg, 537 with edoxaban 30 mg, and 4142 with warfarin. The median CHA. Edoxaban 60 mg is a safe and effective treatment compared with warfarin for stroke prevention in routine clinical care for Danish (mainly Caucasian) patients with AF, with non-significantly different risks for stroke and clinically relevant bleeding, but lower all-cause mortality.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Cohort Studies; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Pyridines; Stroke; Thiazoles; Thromboembolism; Treatment Outcome; Warfarin

Patients with atrial fibrillation and previous ischemic stroke (IS) are at increased risk of cerebrovascular events despite anticoagulation. In these patients, treatment with non-vitamin K oral anticoagulants (NOAC) such as edoxaban reduced the probability and severity of further IS without increasing the risk of major bleeding. However, the detailed protective mechanism of edoxaban has not yet been investigated in a model of ischemia/reperfusion injury. Therefore, in the current study we aimed to assess in a clinically relevant setting whether treatment with edoxaban attenuates stroke severity, and whether edoxaban has an impact on the local cerebral inflammatory response and blood-brain barrier (BBB) function after experimental IS in mice. Focal cerebral ischemia was induced by transient middle cerebral artery occlusion in male mice receiving edoxaban, phenprocoumon or vehicle. Infarct volumes, functional outcome and the occurrence of intracerebral hemorrhage were assessed. BBB damage and the extent of local inflammatory response were determined. Treatment with edoxaban significantly reduced infarct volumes and improved neurological outcome and BBB function on day 1 and attenuated brain tissue inflammation. In summary, our study provides evidence that edoxaban might exert its protective effect in human IS by modulating different key steps of IS pathophysiology, but further studies are warranted.

Topics: Animals; Blood-Brain Barrier; Brain Ischemia; Disease Models, Animal; Humans; Infarction, Middle Cerebral Artery; Inflammation; Mice; Pyridines; Severity of Illness Index; Stroke; Thiazoles

Non-vitamin K oral anticoagulants are safe and effective for stroke prevention in patients with atrial fibrillation (AF). Data on the safety and efficacy of edoxaban in routine care are limited in Europe. We report 1-year outcomes in patients with AF treated with edoxaban in routine care.. ETNA-AF-Europe is a prospective, multicentre, post-authorization, observational study enrolling patients treated with edoxaban in 10 European countries, the design of which was agreed with the European Medicines Agency as part of edoxaban's post-approval safety plan. Altogether 13 092 patients in 852 sites completed the 1-year follow-up [mean age: 73.6 ± 9.5 years; 57% male, mean follow-up: 352 ± 49 days (median: 366 days)]. Most patients had associated comorbidities (mean CHA2DS2-VASc score: 3.1 ± 1.4). Stroke or systemic embolism was reported in 103 patients (annualized event rate: 0.82%/year), and major bleeding events were reported in 132 patients (1.05%/year). Rates of intracranial haemorrhage were low [30 patients (0.24%/year)]. Death occurred in 442 patients (3.50%/year); cardiovascular (CV) death occurred in 206 patients (1.63%/year). The approved dosing of edoxaban was chosen in 83%. All-cause and CV mortality were higher in patients receiving edoxaban 30 mg vs. 60 mg, in line with the higher age and more frequent comorbidities of the 30 mg group. Major bleeding was also numerically more common in patients receiving edoxaban 30 mg vs. 60 mg.. The rates of stroke, systemic embolism, and major bleeding are low in this large unselected cohort of high-risk AF patients routinely treated with edoxaban.

Topics: Aged; Aged, 80 and over; Atrial Fibrillation; Europe; Factor Xa Inhibitors; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prospective Studies; Pyridines; Stroke; Thiazoles

The purpose of the present study was to compare the long-term effectiveness and safety of newly initiated anticoagulation with edoxaban (EDO) versus uninterrupted vitamin K antagonist (VKA) therapy in patients with atrial fibrillation (AF) scheduled for transesophageal echocardiogram (TEE)-guided direct electrical current cardioversion (DCC).. A propensity score-matched cohort observational study was performed comparing the safety and effectiveness of edoxaban versus well-controlled VKA therapy among a cohort of consecutive non-valvular AF patients scheduled for DCC. The primary safety outcome was major bleeding. The primary efficacy outcome was the composite of stroke, transient ischemic attack (TIA), and systemic embolism (SE).. A total of 130 AF patients receiving edoxaban 60-mg (EDO) treatment were compared with the same number of VKA recipients. The cumulative incidence of major bleedings was 1.54% in the EDO group and 3.08% in the VKA group (P = 0.4). The cumulative incidence of thromboembolic events was 1.54% in the EDO group and 2.31% in the VKA group (P = 0.9). A non-significant trend in improved adherence was observed between the EDO and VKA groups with a total anticoagulant therapy discontinuation rate of 4.62% (6/130) vs 6.15% (8/130), respectively (P = 0.06).. Our study provides the evidence of a safe and effective use of edoxaban in this clinical setting, justified by no significant difference in major bleedings and thromboembolic events between edoxaban and well-controlled VKA treatments.

Topics: Aged; Aged, 80 and over; Atrial Fibrillation; Electric Countershock; Embolism; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Ischemic Attack, Transient; Male; Medication Adherence; Middle Aged; Propensity Score; Pyridines; Stroke; Thiazoles; Vitamin K

Recently, guidelines recommended the use of direct oral anticoagulants (DOACs) for the management of non-valvular atrial fibrillation (NVAF). Postoperative atrial fibrillation (POAF) is the most common post-surgical complication of cardiac surgery, but the efficacy and safety of DOAC for POAF have rarely been investigated. We conducted a prospective observational study to investigate the efficacy and safety of DOAC administered immediately after POAF.. In all, 135 patients that experienced POAF after cardiac surgery were treated with a DOAC. Primary endpoints were either bleeding or thromboembolic events. Secondary endpoints included changes in hemoglobin (Hb), prothrombin time (PT), activated partial thromboplastin time (APTT), serum creatinine (sCr), estimated glomerular filtration rate (eGFR), and pleural/pericardial effusion.. Patients were treated with apixaban (n = 31), edoxaban (n = 87), and rivaroxaban (n = 17). Major bleeding (p = 0.011) and gastrointestinal (GI) bleeding (p = 0.047) were significantly more frequent in the rivaroxaban group. Stroke was observed in one rivaroxaban group patient and none in the other two groups.. DOAC as anticoagulation therapy for the early intervention of POAF following cardiac surgery is associated with a low incidence of major bleeding; a favorable safety profile and excellent efficacy were demonstrated for DOAC. Furthermore, our results indicate that the safety and efficacy of apixaban and edoxaban are better than rivaroxaban.

Topics: Aged; Atrial Fibrillation; Cardiac Surgical Procedures; Drug Administration Schedule; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Prospective Studies; Pyrazoles; Pyridines; Pyridones; Risk Factors; Rivaroxaban; Stroke; Thiazoles; Time Factors; Treatment Outcome

In patients with atrial fibrillation, incomplete adherence to anticoagulants increases risk of stroke. Non-warfarin oral anticoagulants (NOACs) are expensive; we evaluated whether higher copayments are associated with lower NOAC adherence.. Using a national claims database of commercially-insured patients, we performed a cohort study of patients with atrial fibrillation who newly initiated a NOAC from 2012 to 2018. Patients were stratified into low (<$35), medium ($35-$59), or high (≥$60) copayments and propensity-score weighted based on demographics, insurance characteristics, comorbidities, prior health care utilization, calendar year, and the NOAC received. Follow-up was 1 year, with censoring for switching to a different anticoagulant, undergoing an ablation procedure, disenrolling from the insurance plan, or death. The primary outcome was adherence, measured by proportion of days covered (PDC). Secondary outcomes included NOAC discontinuation (no refill for 30 days after the end of NOAC supply) and switching anticoagulants. We compared PDC using a Kruskal-Wallis test and rates of discontinuation and switching using Cox proportional hazards models.. After weighting patients across the 3 copayment groups, the effective sample size was 17,558 patients, with balance across 50 clinical and demographic covariates (standardized differences <0.1). Mean age was 62 years, 29% of patients were female, and apixaban (43%), and rivaroxaban (38%) were the most common NOACs. Higher copayments were associated with lower adherence (P < .001), with a PDC of 0.82 (Interquartile range [IQR] 0.36-0.98) among those with high copayments, 0.85 (IQR 0.41-0.98) among those with medium copayments, and 0.88 (IQR 0.41-0.99) among those with low copayments. Compared to patients with low copayments, patients with high copayments had higher rates of discontinuation (hazard ratio [HR] 1.13, 95% confidence interval [CI] 1.08-1.19; P < .001).. Among atrial fibrillation patients newly initiating NOACs, higher copayments in commercial insurance were associated with lower adherence and higher rates of discontinuation in the first year. Policies to lower or limit cost-sharing of important medications may lead to improved adherence and better outcomes among patients receiving NOACs.

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Cohort Studies; Dabigatran; Databases, Factual; Deductibles and Coinsurance; Drug Costs; Factor Xa Inhibitors; Female; Humans; Male; Medicare Part C; Medication Adherence; Middle Aged; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Sample Size; Stroke; Thiazoles; United States; Warfarin

Okumura K, Akao M, Yoshida T, et al.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Embolism; Humans; Pyridines; Stroke; Thiazoles; Treatment Outcome

So far, the only available data for edoxaban periprocedural management come from the ENGAGE AF-TIMI 48 trial. The recently published EMIT-AF/VTE study showed low periprocedural bleeding and thromboembolic risks of edoxaban in a real-world setting in patients undergoing any diagnostic or therapeutic procedures. The aim of this study was to compare descriptively Italian and European data with regard to patient characteristics and outcomes in the EMIT-AF/VTE study.. A total of 1155 patients treated with edoxaban for stroke prevention in non-valvular atrial fibrillation and with venous thromboembolism, and undergoing a wide range of diagnostic and therapeutic procedures were enrolled in 326 centers across Europe. Of these patients, 246 were from 43 Italian centers. The periprocedural interruption of edoxaban was at the physician's discretion. All the procedures were classified into minor, low, and high bleeding procedural risk according to the European Heart Rhythm Association (EHRA) definition. The primary outcome was the incidence of major bleeding. Secondary outcomes included thromboembolic events.. Patients were older in Italy in comparison with the rest of Europe with a mean age of 74.2 vs 71.3 years. Also, the rate of comorbidities was higher in Italy (e.g. diagnosed cancer and vascular disease) than in Europe. In Italy, there was a higher rate of high bleeding risk procedures than in other European countries (37.8% vs 20.6%) and a more homogeneous distribution of all types of procedures (while in Europe 44.1% were vascular access and transcatheter diagnostic procedures and interventions). In Italy, a higher proportion of patients did not interrupt edoxaban (32.9% vs 29% in Europe). The number of major bleeding events (2 in Italy, 3 in Europe) as well as of thromboembolic events (4 in Italy, 3 in Europe) was overall low.. In the EMIT-AF/VTE study, the number of bleeding and thromboembolic events in patients treated with edoxaban undergoing elective or unplanned procedures was low either in Italy or in the rest of Europe. The safety and efficacy of edoxaban was confirmed in Italy even if patients were older, presented more frequently with cancer, and there was a higher rate of high bleeding risk procedures by EHRA definition.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Hemorrhage; Humans; Italy; Pyridines; Stroke; Thiazoles; Venous Thromboembolism

Topics: Aged; Atrial Fibrillation; Humans; Pyridines; Stroke; Thiazoles

Direct oral anticoagulants (DOACs) have replaced vitamin K antagonists as the standard of care for stroke prevention in patients with atrial fibrillation (AF). However, DOAC prescriptions at dosages that do not adhere to labeling are common in daily practice. This analysis from the observational Global Edoxaban Treatment in routiNe clinical prActice (ETNA)-AF program focuses on edoxaban-treated patients from South Korea and Taiwan to identify patient baseline characteristics that may be associated with non-recommended dosing.. We report baseline data from ETNA-AF, including patient demographics, clinical characteristics, and bleeding/stroke history of patients receiving recommended or non-recommended edoxaban dosing.. A total of 2677 patients were enrolled. Among 1543 patients who did not meet dose-reduction criteria, 1033 (66.9%) were prescribed the recommended 60-mg dose, and 510 (33.1%) were prescribed the non-recommended 30-mg dose. Among 1134 patients meeting ≥1 of the dose-reduction criteria, 863 (76.1%) were prescribed the recommended 30-mg dose; 271 (23.9%) were prescribed the nonrecommended 60-mg dose. Compared with the recommended 60-mg group, the nonrecommended 30-mg group had a higher proportion of patients aged ≥75 years, higher stroke and bleeding risks, and a history of major bleeding. The non-recommended 60-mg group had a lower proportion of patients aged ≥75 years, a higher history of stroke, and lower history of bleeding compared with the recommended 30-mg group.. The baseline data from ETNA-AF indicate that physicians take patient clinical characteristics (e.g., bleeding risks) into consideration when deviating from the dosing recommendation per label.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Databases, Factual; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Pyridines; Republic of Korea; Stroke; Taiwan; Thiazoles

Recent data suggest direct oral anticoagulants are as safe and efficacious as warfarin among select patients with valvular heart disease and atrial fibrillation (AF). However, real-world treatment patterns of AF stroke prophylaxis in the setting of valvular AF are currently unknown. Accordingly, using the prospective, ambulatory National Cardiovascular Data Registry Practice Innovation and Clinical Excellence (PINNACLE) Registry, we sought to characterize overall use, temporal trends in use, and the extent of practice-level variation in the use of any direct oral anticoagulant and warfarin among patients with valvular AF from January 1, 2013, to March 31, 2019.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Humans; Male; Practice Patterns, Physicians'; Pyrazoles; Pyridines; Pyridones; Registries; Risk Factors; Rivaroxaban; Stroke; Thiazoles; Warfarin

Direct oral anticoagulants (DOACs) may increase the risk of gastrointestinal (GI) bleeding in patients with atrial fibrillation (AF) and GI cancer compared with vitamin K antagonists (VKA).. We conducted a Danish nationwide cohort study comparing the bleeding risk associated with DOAC versus VKA in patients with AF and GI cancer. We calculated crude bleeding rates per 100 person-years (PYs) for GI and major bleeding. We then compared rates of bleeding at 1 year after initial oral anticoagulation filled prescription by treatment regimen using inverse probability of treatment weighting and Cox regression.. The unweighted study population included 1476 AF patients with GI cancer (41.6% women, median age 78 years) initiating a DOAC and 652 initiating a VKA. One-year risk of GI bleeding was 5.0% in the DOAC group and 4.7% in the VKA group with a corresponding weighted hazard ratio (HR) of 0.95 (95% confidence interval [CI]: 0.63, 1.45). For patients with active cancer, weighted GI bleeding rates were slightly higher in both the VKA and DOAC group, and the weighted HR was 1.00 (95% CI: 0.53, 1.88). The HR was 1.12 (95% CI: 0.71, 1.76) for all bleedings. Hazard ratios for GI bleeding were 0.61 (95% CI: 0.25, 1.52) for patients with upper GI cancer, and 0.92 (95% CI: 0.58, 1.46) in patients with colorectal cancer.. Evidence from this nationwide cohort study suggests a comparable 1-year risk of bleeding associated with DOAC compared with VKA among patients with AF and GI cancer.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cohort Studies; Confidence Intervals; Dabigatran; Denmark; Factor Xa Inhibitors; Female; Gastrointestinal Neoplasms; Hemorrhage; Humans; Male; Proportional Hazards Models; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Warfarin

 Nonvitamin K antagonist oral anticoagulants (NOACs) require stricter medication adherence. We investigated the NOACs adherence in real-world practice..  We screened all patients in our cardiology department the day before their outpatient appointment, over a 5-month period. We enrolled 719 consecutive patients who were taking NOACs for atrial fibrillation. The patients were contacted by phone or text to bring the remnant pills with them without any information why. Adherence was measured by the percentage of prescribed doses taken (PDT) (number of doses taken/number of doses expected to be taken from the last prescription × 100 [%]) and the Morisky Medication Adherence Scale (MMAS)-8..  Most patients who were taking NOACs had excellent adherence regardless of the dosing frequency. An MMAS ≥ 3 could be used as a simple screening tool for a poor NOAC adherence.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Cross-Sectional Studies; Dabigatran; Drug Administration Schedule; Female; Humans; Male; Medication Adherence; Middle Aged; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Surveys and Questionnaires; Thiazoles

Empirically, a significant proportion of patients using direct oral anticoagulation (DOAC) take off-label reduced doses. We aimed to investigate the prevalence, indications, dosages, and bleeding complications of oral anticoagulants on admission to the emergency department.. In this retrospective analysis, patients presenting to our emergency department between January 1 and December 31, 2018, with therapeutic oral anticoagulation were included (ie, vitamin-K antagonists, rivaroxaban, apixaban, edoxaban, and dabigatran). A detailed chart review was performed for each case concerning characteristics, indication, and bleeding complications.. A total of 19,662 consecutive cases in the emergency department were reported: 1721 (9%) had therapeutic oral anticoagulation. Vitamin-K antagonists (41%), rivaroxaban (36%), and apixaban (19%) were the most common. Stroke prophylaxis in patients with atrial fibrillation (63.2%) and venous thromboembolism (24.1%) were the most common indications. In 27 cases (1.6%), no indication could be identified; further, 32% of patients were classified to have either off-label doses of DOACs or an international normalized ratio (INR) out of range (in vitamin-K antagonists), whereas 20% were classified as off-label underdosed and 12% as overdosed. No difference in the likelihood of bleeding on admission could be found between the respective drugs. Only concomitant use of aspirin was significantly associated with presence and higher severity of bleeding.. Vitamin-K antagonists are still the most widely used drug followed by rivaroxaban. A significant proportion of patients are being prescribed off label-doses. While no difference was found for the respective anticoagulants with respect to bleeding, concomitant aspirin use was a significant predictor for bleeding in our collective.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Emergency Service, Hospital; Female; Hemorrhage; Humans; Male; Off-Label Use; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Thiazoles; Vitamin K

Non-vitamin K antagonist oral anticoagulants represent a new option for prevention of embolic events in patients with atrial fibrillation (AF). However, little is known about the impact of non-cardiac comorbidities on the efficacy and safety profile of these drugs.. In a post hoc analysis of the ENGAGE AF-TIMI 48 trial, we analysed 21 105 patients with AF followed for an average of 2.8 years and randomized to either a higher-dose edoxaban regimen (HDER), a lower-dose edoxaban regimen, or warfarin. We used the updated Charlson Comorbidity Index (CCI) to stratify the patients according to the burden of concomitant disease (CCI = 0, 1, 2, 3, and ≥4). The treatment groups were then compared for safety, efficacy, and net clinical outcomes across CCI categories. There were 32.0%, 7.3%, 42.1%, 12.7%, and 6.0% of patients with CCI scores of 0, 1, 2, 3, and ≥4, respectively. A CCI score ≥4 was associated with significantly higher rates of thromboembolic events, bleeding, and death compared to CCI = 0 (P < 0.05 for each). The annualized rates of the primary net clinical outcome (stroke/systemic embolism, major bleeding, or death) for CCI = 0, 1, 2, 3, or ≥4 were 5.9%, 8.7%, 6.6%, 10.3%, and 13.6% (Ptrend < 0.001). There were no significant interactions between treatment with HDER vs. warfarin and efficacy, safety, and net outcomes across the CCI groups (P-interaction > 0.10 for each).. Although increasing CCI scores are associated with worse outcomes, the efficacy, safety, and net clinical outcomes of edoxaban vs. warfarin were independent of the degree of comorbidity present.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Comorbidity; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Pyridines; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Stroke; Thiazoles; Thromboembolism; Time Factors; Treatment Outcome; Warfarin

ENSURE-AF (NCT02072434) assessed therapy with edoxaban vs enoxaparin-warfarin in patients with nonvalvular atrial fibrillation (AF) undergoing elective electrical cardioversion (ECV).. To evaluate clinical features and primary efficacy (composite of stroke, systemic embolic events, myocardial infarction and cardiovascular mortality during study period) and safety endpoints (composite of major and clinically relevant nonmajor bleeding during on-treatment period) in patients awaiting ECV of AF with a transesophageal echocardiography (TEE)-guided vs a non-TEE-guided strategy.. In this prospective, randomized, open-label, blinded endpoint study, 2199 patients were randomized to edoxaban 60 mg once-daily (30 mg for creatinine clearance 15-50 mL/min, weight ≤60 kg and/or concomitant use of P-glycoprotein inhibitor) or enoxaparin-warfarin. Primary efficacy endpoint and safety endpoint were reported. Associates of TEE use, efficacy endpoint and safety endpoint were explored using multivariable logistic regression.. In total, 589 patients from the edoxaban stratum and 594 from the enoxaparin-warfarin stratum were allocated to the TEE-guided strategy. Primary efficacy was similar regardless of TEE approach (P = .575). There were no significant differences in bleeding rates, regardless of TEE approach (P = .677). Independent predictors of TEE use were as follows: history of ischaemic stroke/ transient ischaemic attack, hypertension and valvular heart disease. Mean CHA. Thromboembolic and bleeding events were not different between patients undergoing TEE-guided strategy and in those undergoing an optimized conventional anticoagulation approach for ECV of AF.

Topics: Aged; Anticoagulants; Atrial Appendage; Atrial Fibrillation; Clinical Decision-Making; Duration of Therapy; Echocardiography, Transesophageal; Electric Countershock; Enoxaparin; Female; Heart Diseases; Humans; International Normalized Ratio; Male; Middle Aged; Pyridines; Randomized Controlled Trials as Topic; Stroke; Thiazoles; Thrombosis; Warfarin

Edoxaban is an oral anticoagulant drug and a direct factor Xa inhibitor. However, it is still not fully understood if and how edoxaban impacts platelet function. This prospective study aimed to assess in vitro platelet function in patients with atrial fibrillation (AF) receiving edoxaban. It was a single centre study quantifying platelet aggregation in 20 patients treated with edoxaban by light transmission aggregometry. The thrombin receptor activating peptide (TRAP)-induced platelet aggregation was significantly lower 2 h after taking edoxaban compared to baseline value (44.7 ± 32.03% vs. 73.3 ± 25.55%; p < 0.0001). In addition, we did not find any significant difference in results between the patient groups.The TRAP-induced platelet aggregation is reduced in non-valvular AF patients receiving edoxaban.

Topics: Adult; Aged; Aged, 80 and over; Atrial Fibrillation; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Platelet Aggregation; Prospective Studies; Pyridines; Stroke; Thiazoles

Novel biomarkers are desired to improve risk management for patients with atrial fibrillation (AF). We measured 179 plasma miRNAs in 83 AF patients using multiplex qRT-PCR. Plasma levels of eight (i.e., hsa-miR-22-3p, hsa-miR-128-3p, hsa-miR-130a-3p, hsa-miR-140-5p, hsa-miR-143-3p, hsa-miR-148b-3p, hsa-miR-497-5p, hsa-miR-652-3p) and three (i.e., hsa-miR-144-5p, hsa-miR-192-5p, hsa-miR-194-5p) miRNAs showed positive and negative correlations with CHA

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Biomarkers; Catheter Ablation; Circulating MicroRNA; Decision Making; Female; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Humans; Male; Middle Aged; Pyridines; Stroke; Thiazoles

Oral anticoagulants are prescribed for stroke prophylaxis in patients with atrial fibrillation, which is the most common heart arrhythmia worldwide. The vitamin K antagonist (VKA) warfarin is a long-established anticoagulant. However, newer direct oral anticoagulants (DOACs) have been recently introduced as an alternative. Given the prevalence of atrial fibrillation, anticoagulant choice has substantial clinical and financial implications for healthcare systems. In this study, we explore trends and geographic variation in anticoagulant prescribing in English primary care. Because national guidelines in England do not specify a first-line anticoagulant, we investigate the association between local policies and prescribing data.. Primary care prescribing data of anticoagulants for all NHS practices from 2014 to 2019 in England was obtained from the ePACT2 database. Public formularies were accessed online to obtain local anticoagulation prescribing policies for 89.5% of clinical commissioning groups (CCGs). These were categorized according to their recommendations: no local policies, warfarin as first-line, or identification of a preferred DOAC (but not a preferred anticoagulant). Local policies were cross-tabulated with pooled prescribing data to measure the strength of association with Cramér's V.. Nationally, prescribing of DOACs increased from 9% of all anticoagulants in 2014 to 74% in 2019, while that of warfarin declined accordingly. Still, there was significant local variation. Across geographical regions, DOACs ranged from 53 to 99% of all anticoagulants. Most CCGs (73%) did not specify a first-line choice, and 16% recommended warfarin first line. Only 11% designated a preferred DOAC. Policies with a preferred DOAC indeed correlated with increased prescribing of that DOAC (Cramér's V = 0.25, 0.27, 0.38 for rivaroxaban, apixaban, edoxaban respectively). However, local policies showed a negligible relationship with the classes of anticoagulants prescribed-DOAC or VKA (Cramér's V = 0.01).. Nationally, the use of DOACs to treat atrial fibrillation has increased rapidly. Despite this, significant geographical variation in uptake remains. This study provides insights on how local policies relate to this variation. Our findings suggest that, in the absence of a nationally recommended first-line anticoagulant, local prescribing policies may aid in deciding between individual DOACs, but not in adjudicating between DOACs and vitamin K antagonists (i.e. warfarin) as general classes.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Drug Utilization; England; Female; Humans; Male; Practice Patterns, Physicians'; Primary Health Care; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; State Medicine; Stroke; Thiazoles; Warfarin

The evolution of non-vitamin K antagonist anticoagulants (NOACs) has changed the horizon of stroke prevention in atrial fibrillation (SPAF). All 4 NOACs have been tested against dose-adjusted warfarin in well-designed, pivotal, phase III, randomized, controlled trials (RCTs) and were approved by regulatory authorities for an SPAF indication. However, as traditional RCTs, these trials have important weaknesses, largely related to their complex structure and patient participation, which was limited by strict inclusion and extensive exclusion criteria. In the real world, however, clinicians are often faced with complex, multimorbid patients who are underrepresented in these RCTs. This article is based on a meeting report authored by 12 scientists studying atrial fibrillation (AF) in diverse ways who discussed the management of challenging AF cases that are underrepresented in pivotal NOAC trials.. An advisory board panel was convened to confer on management strategies for challenging AF cases. The article is derived from a summary of case presentations and the collaborative discussions at the meeting.. This expert consensus of cardiologists aimed to define management strategies for challenging cases with patients who underrepresented in pivotal trials using case examples from their routine practice. Although strong evidence is lacking, exploratory subgroup analysis of phase III pivotal trials partially informs the management of these patients. Clinical trials with higher external validity are needed to clarify areas of uncertainty. The lack of clear evidence about complex AF cases has pushed clinicians to manage patients based on clinical experience, including rare situations of off-label prescriptions.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cardiologists; Clinical Trials, Phase III as Topic; Consensus; Dabigatran; Disease Management; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiazoles; Vitamin K; Warfarin

Edoxaban is licensed in many countries around the world, following successful phase-III trials in stroke prevention in atrial fibrillation (SPAF) and treatment of venous thromboembolism (VTE), but at present, little is known about edoxaban-related bleeding complications in daily care. Using data from a prospective, non-interventional oral anticoagulation registry, we analysed rates, management and outcome of edoxaban-related bleeding. Between 1 October 2011 and 28 February 2019, 996 patients were enrolled in the edoxaban cohort and a total of 891 bleeding events were observed (53.2% ISTH minor, 41.9% clinically relevant non-major and 4.9% major bleeding events). In case of major bleeding, surgical or interventional treatment was performed in 25.0% and prothrombin complex concentrate was given in 2 cases. In the time-to-first-event analysis, 100-patient-year rates of major bleeding were 3.1/100 patient-years (95% CI 2.2-4.2). In the as-exposed analysis, case-fatality rates of edoxaban-associated bleeding leading to hospitalizations were 7.5% and 9.0% at days 30 and 90 post bleeding, respectively. Taken together, our data indicate that, in real life, rates of edoxaban-related major bleeding in line with rates observed in phase III trials and that bleeding pattern, management and outcome of these events are not different from those reported for other direct factor Xa inhibitors. Clinical Trial Notation: Dresden NOAC Registry - ClinicalTrials.gov Identifier NCT01588119.

Topics: Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Humans; Prospective Studies; Pyridines; Registries; Stroke; Thiazoles; Treatment Outcome

To assess the safety (ie, risk of bleeding) and effectiveness (ie, risk of stroke/systemic embolism (SE)) separately for four non-vitamin K oral anticoagulants (NOACs; apixaban, dabigatran, edoxaban and rivaroxaban) versus warfarin in Japanese patients with non-valvular atrial fibrillation (NVAF), including those at high risk of bleeding and treated with reduced doses of NOACs.. We conducted a retrospective analysis of electronic health records and claims data from 372 acute care hospitals in Japan for patients with NVAF newly initiated on NOACs or warfarin. Baseline characteristics were balanced using inverse probability of treatment weighting with stabilised weights (s-IPTW). Bleeding risk and stroke/SE risk were expressed as HRs with 95% CIs. Two sensitivity analyses were conducted.. In patients with NVAF primarily treated with reduced-dose NOACs, the risks of stroke/SE and major bleeding were significantly lower with NOACs versus warfarin.

Topics: Administration, Oral; Administrative Claims, Healthcare; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Electronic Health Records; Female; Hemorrhage; Humans; Japan; Male; Middle Aged; Patient Safety; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Risk Assessment; Risk Factors; Rivaroxaban; Stroke; Thiazoles; Time Factors; Treatment Outcome; Vitamin K; Warfarin

The evidence of effectiveness and safety of the non-vitamin K antagonist oral anticoagulants (NOACs) among elderly East Asians is limited.. We aimed to describe the effectiveness and safety outcomes associated with NOACs and warfarin among elderly Koreans aged ≥80 years.. Using the Korean Health Insurance Review and Assessment service database, patients with atrial fibrillation (AF) who were naïve to index oral anticoagulant between 2015 and 2017 were included in this study (20,573 for NOACs and 4086 for warfarin). Two treatment groups were balanced using the inverse probability of treatment weighting (IPTW) method. The clinical outcomes including ischemic stroke, major bleeding including intracranial hemorrhage (ICH) and gastrointestinal bleeding (GIB), and a composite of these outcomes were evaluated.. Compared to warfarin, NOACs were associated with lower risks of ischemic stroke (hazard ratio 0.74 [95% confidence interval 0.62-0.89]), and composite outcome (0.78 [0.69-0.90]). NOACs showed nonsignificant trends towards to lower risks of GIB and major bleeding than warfarin. The risk of ICH of NOAC group was comparable with the warfarin group. Among NOACs, apixaban and edoxaban showed better composite outcomes than warfarin. Among the clinical outcomes, only ischemic stroke and the composite outcome had a significant interaction with age subgroups (80-89 years and ≥90 years, P-for-interaction = .097 and .040, respectively).. NOACs were associated with lower risks of ischemic stroke and the composite outcome (ischemic stroke and major bleeding) compared to warfarin in elderly East Asians. Physicians should be more confident in prescribing NOACs to elderly East Asians with AF.

Topics: Aged, 80 and over; Atrial Fibrillation; Brain Ischemia; Databases, Factual; Factor Xa Inhibitors; Female; Gastrointestinal Hemorrhage; Humans; Intracranial Hemorrhages; Male; Pyrazoles; Pyridines; Pyridones; Republic of Korea; Stroke; Thiazoles; Vitamin K; Warfarin

The effect of edoxaban on plasma prothrombin fragment 1+2 (PTF1+2), a sensitive maker of in vivo thrombin generation, has not been fully investigated in nonvalvular atrial fibrillation (NVAF). We compared plasma PTF1+2 levels between 25 NVAF patients receiving warfarin and 100 NVAF patients receiving edoxaban and additionally analyzed the association between plasma PTF1+2 levels and the dose of edoxaban. Plasma PTF1+2 levels were significantly higher in patients receiving edoxaban than in those receiving warfarin (141.5 ± 50.0 pmol/l vs 93.1 ± 55.7 pmol/l, p < 0.001). The prevalence of plasma PF1+2 levels above the upper limit (229 pmol/l) of the normal range did not differ between the 2 groups (4% vs 4%), whereas the prevalence of plasma PTF1+2 levels below the lower limit (69 pmol/l) of the normal range was significantly lower in patients receiving edoxaban than in those receiving warfarin (1% vs 48%, p < 0.001). Multiple linear regression analysis identified age and warfarin treatment as independent variables associated with the plasma PTF1+2 level. In a subgroup analysis, plasma PTF1+2 levels were significantly higher in 58 receiving edoxaban of 30 mg/day than in 42 receiving edoxaban of 60 mg/day (157.6 ± 50.8 pmol/l vs 121.6 ± 39.8 pmol/l, p = 0.01); however, after adjusting for confounding factors, the dose of edoxaban was not independently associated with the plasma PTF1+2 level. In conclusion, edoxaban sufficiently inhibits thrombin generation unrelated to its dose in NVAF, although its inhibitory effect is weaker compared with warfarin.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Female; Humans; Male; Peptide Fragments; Prospective Studies; Prothrombin; Pyridines; Stroke; Thiazoles; Warfarin

Direct oral anticoagulants (DOAC) are mostly prescribed to prevent cardioembolic stroke in patients with non-valvular atrial fibrillation (AF). An increasing number of guidelines recommend DOAC in AF patients with preserved renal function for the prevention of thromboembolism, and an increased use of DOAC in daily practice has been recorded also in elderly patients. Ageing is associated with a reduction in glomerular filtration rate, and impaired renal function, regardless of the cause, increases the risk of bleeding. Multiple medication use (polypharmacy) for treating superimposed co-morbidities is common in both elderly and chronic kidney disease (CKD) patients and drug-drug interaction may cause accumulation of DOAC, thereby increasing the risk of bleeding. The safety profile of DOAC in patients with CKD has not been defined with any certainty, particularly in those with severely impaired renal function or end stage renal disease. This has been due to the heterogeneity of studies and the relative paucity of data. This document reports the position of three Italian scientific societies engaged in the management of patients with atrial fibrillation who are treated with DOAC and present with CKD.

Topics: Administration, Oral; Antidotes; Antithrombins; Atrial Fibrillation; Cohort Studies; Dabigatran; Drug Interactions; Drug Monitoring; Glomerular Filtration Rate; Hemorrhage; Humans; Kidney; Metabolic Clearance Rate; Observational Studies as Topic; Polypharmacy; Practice Guidelines as Topic; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Rivaroxaban; Stroke; Thiazoles

Topics: Aged; Atrial Fibrillation; Humans; Pyridines; Stroke; Thiazoles

Atrial fibrillation (AF) is the most common form of arrhythmia worldwide and a significant health burden. Edoxaban, a recent novel oral anticoagulant (NOAC), is being investigated in the European real-world ETNA-AF study of patients with non-valvular atrial fibrillation (NVAF). The aim of this study was to characterize the Iberian edoxaban-treated cohort of ETNA-AF at baseline and to compare it with previously retrieved Portuguese data.. Patients with NVAF treated with edoxaban and followed in Portuguese and Spanish centers were consecutively enrolled between June 2017 and January 2018. Only patients with a previous clinical decision to receive edoxaban were included. Patients' baseline demographic and clinical parameters, medical history, and AF-related characteristics were retrieved.. A total of 892 NVAF patients, with a mean age of 73.9 years, were included, 75.3% of whom received high-dose (60 mg) and 24.7% low-dose (30 mg) edoxaban. Most patients (55.9%) were male. Of the patients receiving 30 mg and 60 mg edoxaban, 55.9% and 37.9%, respectively, had an estimated CHA. This study provides valuable data on disease and patient profiles and will provide valuable insights into disease management and progression, as well as the safety, effectiveness, and patterns of cardiovascular events associated with edoxaban.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Humans; Male; Pyridines; Stroke; Thiazoles

Antiplatelet therapy (APT) use in combination with oral anticoagulation is common among patients with atrial fibrillation, but there is scarce information regarding its effect on outcomes in patients on non-vitamin K antagonist oral anticoagulants (NOAC). We aimed to evaluate the safety and efficacy of APT use in a 'real-world' cohort of nonvalvular atrial fibrillation (NVAF) patients initiating NOAC.. We conducted a retrospective multicentre study including 2361 consecutive NVAF patients initiating NOAC between January 2013 and December 2016. Patients with an acute ischaemic event within the last 12 months (acute coronary syndrome, stroke or revascularization) were excluded. Patients were followed up, and all clinical events were recorded at 3 months. The primary outcome of the study was major bleeding, and the secondary outcomes were stroke, nonfatal myocardial infarction, intracranial bleeding and death.. One hundred forty-five (6.1%) patients received concomitant APT, and aspirin was the more common (79%). At 3 months, 25 (1.1%) patients had major bleeding, 8 (0.3%) had nonfatal myocardial infarction, 7 (0.3%) had ischaemic stroke, and 40 (1.7%) died. After multivariate adjustment, concomitant APT was associated with higher risk for major bleeding (HR = 3.62, 95% CI 1.32-9.89; P = .012), but was not associated with a higher risk of other clinical outcomes.. Concomitant APT use is uncommon among these patients and does not seem to be associated with lower rates of ischaemic events or death. However, there are signals for an increased risk of bleeding, which reinforces current guideline recommendations.

Topics: Aged; Aged, 80 and over; Antithrombins; Aspirin; Atrial Fibrillation; Dabigatran; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Mortality; Myocardial Infarction; Platelet Aggregation Inhibitors; Proportional Hazards Models; Purinergic P2Y Receptor Antagonists; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Thiazoles

Treatment with anticoagulants, including direct oral anticoagulants (DOACs), should be considered for patients diagnosed with atrial fibrillation (AF) deemed at risk of ischaemic stroke. There are limited real world data related to the characteristics of patients with non-valvular AF who were not taking anticoagulants at the time of first ischaemic stroke and their subsequent DOAC treatment for the secondary prevention of stroke. Furthermore, little is known about patient adherence and experiences of DOAC treatment, especially for patients with non-valvular AF receiving DOAC therapy for the secondary prevention of stroke.. This is a UK mixed methodology, non-interventional study, involving retrospective and prospective medical record reviews and a prospective patient survey, in progress in six UK National Health Service secondary/tertiary care centres. The study comprises two groups of patients. Group 1 will include 300 eligible consenting patients with a first ischaemic stroke associated with non-valvular AF untreated with anticoagulants in the 12 months prior to stroke. Group 2 will include a subgroup of 150 patients from Group 1 initiated on one of the DOACs targeting activated Factor X (n = 50 on apixaban, n = 50 on edoxaban and n = 50 on rivaroxaban). The primary endpoint of the study is the CHA. This mixed methodology study will provide new real world insights into the characteristics and management pathways and patient-reported experiences of this important group of patients. It is anticipated that the results of this study will provide the medical community and patients with important information to inform clinical decision-making and help facilitate meaningful improvements in the care of patients with non-valvular AF.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Humans; Prospective Studies; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Thiazoles; United Kingdom

Topics: Anticoagulants; Female; Humans; Male; Prothrombin Time; Pyridines; Stroke; Thiazoles; United Kingdom; Venous Thromboembolism

Edoxaban, a nonvitamin K antagonist oral anticoagulant, is an oral factor Xa inhibitor approved for the prevention of stroke and systemic embolism in adult patients with atrial fibrillation and for the treatment and secondary prevention in adult patients with venous thromboembolism (VTE). This study details the design of the Edoxaban Treatment in routiNe clinical prActice for patients with Atrial Fibrillation in Europe (ETNA-AF-Europe) study - a postauthorization observational study, which is part of the postapproval plan for edoxaban agreed with the European Medicines Agency.. The ETNA-AF-Europe study (Clinicaltrials.gov: NCT02944019) is a multicenter, prospective, observational study that enrolled 13 980 patients with atrial fibrillation treated with edoxaban from 852 sites across 10 European countries (Austria, Belgium, Germany, Ireland, Italy, the Netherlands, Portugal, Spain, Switzerland, and the United Kingdom). Patients treated with edoxaban were prospectively enrolled and will be followed up for 4 years with yearly follow-up visits.. The primary objective of the ETNA-AF-Europe study is to assess the real-world safety of edoxaban by evaluating bleeding events, including intracranial hemorrhage; drug-related adverse events, such as hepatic events; and cardiovascular and all-cause mortality. In addition, efficacy will be assessed by recording major adverse cardiovascular events including stroke, systemic embolic events, transient ischemic attacks, and also VTE episodes, acute coronary syndromes, and hospitalizations related to cardiovascular condition. Event rates will be compared with event rates reported in the PREvention oF thromboembolic events-European Registry in Atrial Fibrillation in atrial fibrillation (PREFER in AF) and PREFER in AF Prolongation registries, and in the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation - Thrombolysis in Myocardial Infarction 48 study datasets.

Topics: Administration, Oral; Atrial Fibrillation; Europe; Factor Xa Inhibitors; Hemorrhage; Humans; Prospective Studies; Pyridines; Registries; Research Design; Stroke; Thiazoles; Time Factors; Treatment Outcome

Topics: Asian People; Atrial Fibrillation; Humans; Pyridines; Stroke; Thiazoles

Although novel oral-anticoagulants are widely used in patients with atrial fibrillation (AF) for stroke prevention, there was only limited evidence for their use in left ventricular (LV) thrombus.. A 41-year-old man who presented with acute onset of right-hand clumsiness and aphasia even under high international normalized ratio (INR: 7.64) from warfarin use. He was previously treated with warfarin for the LV thrombus and non-valvular AF. Brain magnetic resonance imaging (MRI) showed multiple acute infarction in the cortex of the bilateral frontal lobes, left parietal lobe, and bilateral central semiovale, which highly suggested embolic stroke.. The repeated transthoracic echocardiogram still revealed LV thrombus (1.27 × 0.90 cm), which failed to respond to warfarin therapy.. Due to acute infarctions occurred under supratherapeutic range of INR, we switched warfarin to edoxaban (dose: 60 mg/day) after INR decreased to less than 2.. The thrombus disappeared after receiving edoxaban for 23 days, and no more recurrent stroke was noted for more than 6 months.. This is the first case demonstrates that while facing ineffective treatment of warfarin for LV thrombus, edoxaban could be safely and effectively used under this situation.

Topics: Adult; Anticoagulants; Brain Ischemia; Heart Failure; Heart Ventricles; Humans; Male; Pyridines; Retreatment; Stroke; Thiazoles; Thrombosis; Warfarin

To analyze the effectiveness and safety of direct oral anticoagulants (DOACs) in atrial fibrillation (AF) patients attended in clinical practice.. Observational and prospective study of AF patients that started treatment with DOACs.. This was the first prospective study that analyzed the use of all DOACs in AF patients in Spain, showing a good profile in terms of safety and effectiveness in accordance with pivotal studies.

Topics: Administration, Oral; Age Factors; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Hemorrhage; Humans; Male; Prospective Studies; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Spain; Stroke; Thiazoles; Treatment Outcome

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Dose-Response Relationship, Drug; Embolism; Humans; Pyrazoles; Pyridines; Pyridones; Research Design; Rivaroxaban; Stroke; Thiazoles

Topics: Administration, Oral; Anticoagulants; Aspirin; Atrial Fibrillation; Dabigatran; Health Services Misuse; Hemorrhage; Humans; International Normalized Ratio; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Septal Occluder Device; Stroke; Thiazoles; Warfarin

Cranial artery dolichoectasia is characterized by dilated, elongated, and tortuous cranial arteries. Dolichoectasia and dolichoectatic aneurysm-particularly of the internal carotid arteries (ICAs)-are rare but can lead to stroke. We report a case of suspected recurrent acute cerebral infarction and dolichoectatic aneurysm of the left ICA combined with right dolichoectatic aneurysm, vertebrobasilar dolichoectasia, and atrial fibrillation.. An 80-year-old man experienced 3 days of recurrent aphasia episodes. He had a history of atrial fibrillation and hypertension. Neurologic findings indicated Wernicke aphasia. Magnetic resonance imaging showed acute cerebral infarction in the left temporal and parietal lobes. Magnetic resonance angiography and cerebral angiography showed dolichoectatic aneurysms in the C1-2 portion of the bilateral ICAs and vertebrobasilar dolichoectasia. Possible diagnoses included convulsion, cardioembolic infarction, atherothrombotic cerebral infarction, and acute ischemic stroke associated with the dolichoectatic aneurysm of the left ICA. Oral antiplatelet drugs, direct oral anticoagulants, and anticonvulsants were administered. Nine months after initial hospitalization, the patient had a recurrence of acute ischemic stroke and was rehospitalized. He was treated with a new direct oral anticoagulant, clopidogrel, statins, and ethyl icosapentate. At 2 years after initial hospitalization, he has had no recurrence of stroke, has a modified Rankin Scale score of 2, and is currently being followed as an outpatient.. A direct oral anticoagulant (edoxaban) and clopidogrel were effective for suspected recurrent acute ischemic stroke associated with dolichoectatic aneurysm of the ICA combined with contralateral dolichoectatic aneurysm, vertebrobasilar dolichoectasia, and atrial fibrillation.

Topics: Aged, 80 and over; Aneurysm; Anticoagulants; Brain Ischemia; Carotid Artery Diseases; Carotid Artery, Internal; Clopidogrel; Humans; Male; Platelet Aggregation Inhibitors; Pyridines; Recurrence; Stroke; Thiazoles; Vertebrobasilar Insufficiency

Vitamin K antagonists (eg, warfarin) have been the standard of care for stroke prophylaxis in atrial fibrillation. The direct oral anticoagulants dabigatran (direct thrombin inhibitor) and rivaroxaban, apixaban, and edoxaban (direct factor Xa inhibitors) are as efficacious as and in some instances superior to vitamin K antagonists in the prevention of stroke, systemic embolism, and major bleeding compared with warfarin for nonvalvular atrial fibrillation. Benefits of direct oral anticoagulants include a rapid onset of therapeutic effect, fixed dose-response relationships without the need for routine monitoring, a short half-life, and infrequent need for periprocedural bridging with a parenteral agent. However, direct oral anticoagulants differ in subsets of patients. Critical care and advanced practice nurses must understand these differences, prescribing considerations, drug aherence interventions, drug-drug interactions, and periprocedural management. This article presents an update and review of direct oral antigcoagulants based on the latest national guidelines.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Critical Care Nursing; Dabigatran; Female; Humans; Male; Middle Aged; Practice Guidelines as Topic; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Warfarin

To assess the cost-effectiveness of edoxaban vs acenocoumarol in the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF) in Spain.. Markov model, adapted to the Spanish setting from the perspective of the National Health System, stimulating the progression of a hypothetical cohort of patients with NVAF throughout their lifetime, with different health states: stroke, haemorrhage, and other cardiovascular complications. Efficacy and safety data were obtained from the available clinical evidence (mainly from the phase III ENGAGE AF-TIMI 48 study). The costs of managing NVAF and its complications were obtained from Spanish sources.. Edoxaban use led to 0.34 additional quality-adjusted life years (QALY) compared with acenocoumarol. The incremental cost with edoxaban was 3916€, mainly because of higher pharmacological costs, which were partially offset by lower costs of treatment monitoring and managing NVAF events and complications. The cost per QALY was 11 518€, within the thresholds commonly considered cost-effective in Spain (25 000-30 000 €/QALY). The robustness of the results was confirmed by various sensitivity analyses.. Edoxaban is a cost-effective alternative to acenocoumarol in the prevention of stroke and systemic embolism in patients with NVAF in Spain.

Topics: Adult; Aged; Aged, 80 and over; Atrial Fibrillation; Cost-Benefit Analysis; Drug Costs; Embolism; Facilities and Services Utilization; Factor Xa Inhibitors; Health Resources; Humans; Male; Middle Aged; Pyridines; Quality of Life; Quality-Adjusted Life Years; Spain; Stroke; Thiazoles

Whether four direct oral anticoagulants (DOACs) are superior to warfarin in Asian patients with nonvalvular atrial fibrillation (NVAF) remains unclear.. This nationwide retrospective cohort study was based on data from Taiwan's National Health Insurance Research Database from June 1, 2012, to December 31, 2017, covering patients with NVAF taking edoxaban (n = 4,577), apixaban (n = 9,952), rivaroxaban (n = 33,022), dabigatran (n = 22,371), and warfarin (n = 19,761). Propensity score weighting was used to balance covariates across study groups. Patients were followed up until occurrence of study outcomes or end date of study.. In the largest real-world practice study among Asian patients with NVAF, four DOACs were associated with a comparable or lower risk of thromboembolism, and a lower risk of bleeding than warfarin. There was consistency even among high-risk subgroups and whether standard-or low-dose regimens were compared.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Asian People; Atrial Fibrillation; Dabigatran; Databases, Factual; Female; Hemorrhage; Humans; Male; Middle Aged; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Taiwan; Thiazoles; Thromboembolism; Treatment Outcome; Warfarin

Topics: Administration, Oral; Aged; Atrial Fibrillation; Biomarkers; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Female; Follow-Up Studies; Humans; Incidence; Japan; Male; Partial Thromboplastin Time; Predictive Value of Tests; Prospective Studies; Prothrombin Time; Pyridines; ROC Curve; Stroke; Thiazoles; Treatment Outcome

The purpose of the current study was to compare the efficacy and safety of edoxaban versus vitamin K antagonist (VKA) therapy among a cohort of elderly patients (ie, those aged ≥75 years) with atrial fibrillation (AF) in a real-life setting.. A propensity score-matched cohort observational study was performed comparing the safety and efficacy of edoxaban versus VKA therapy among a cohort of elderly (aged ≥75 years) patients with AF in a real-life setting. Follow-up data were obtained through outpatient visits at 1, 3, and every 6 months. The primary safety outcome was major bleeding. The primary efficacy outcome was the composite of stroke, transient ischemic attack, and systemic embolism.. A total of 130 patients receiving edoxaban 60 mg (EDO) treatment were compared with the same number of VKA recipients. The mean follow-up was 16 (2.6) months. The cumulative incidence of thromboembolic events in the EDO and VKA groups was 1.5% (2 of 130) and 2.3% (3 of 130), respectively (P < 0.6). The cumulative incidence of major bleeding events was 1.5% (2 of 130) in the EDO group and 3.1% (4 of 130) in the VKA group (P < 0.4). The total anticoagulant therapy discontinuation rate was 2.3% (3 of 130) in the EDO group and 4.6% (6 of 130) in the VKA group (P < 0.3). A nonsignificant trend in improved adherence was observed between the EDO and VKA groups (81% vs 78%; P = 0.6).. Edoxaban therapy showed a good real-life performance among elderly patients (aged ≥75 years) with AF.

Topics: Aged; Aged, 80 and over; Atrial Fibrillation; Cohort Studies; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Ischemic Attack, Transient; Male; Propensity Score; Pyridines; Stroke; Thiazoles; Thromboembolism; Treatment Outcome; Vitamin K

The aim of this study was to evaluate the appropriateness and clinical outcomes of edoxaban use, and to determine the role of clinical pharmacists in improving the efficacy and safety of edoxaban use.. A retrospective study was performed by using an electronic medical record and anticoagulation clinical data from 600 patients who received edoxaban from 1 March 2016 to 16 July 2017 at a tertiary teaching university hospital. The appropriateness of edoxaban use was assessed using eight criteria based on drug use evaluation criteria developed by the American Society of Health-System Pharmacists drug use evaluation guidelines, details in Korea Food and Drug Administration approval of edoxaban. Clinical outcomes were evaluated between the appropriately prescribed and inappropriately prescribed groups regarding the incidence of thrombosis and bleeding episodes.. After excluding 86 patients due to the inability to assess renal function, 514 were eligible. Appropriate use was found in 294 patients (57.2%). The most frequent inappropriate use of edoxaban was dose adjustment (60.8%) in accordance with the dosing recommendation in patients with renal insufficiency (creatinine clearance [CrCl] of 15-50 mL/min) and a low body weight of <60 kg. Moreover, there were three cases of edoxaban use in patients with prosthetic heart valves and moderate-to-severe mitral stenosis, and 15 cases of non-valvular atrial fibrillation in patients with CrCl >95 mL/min in whom edoxaban use is not recommended. Furthermore, we found that the factors related to the appropriateness of edoxaban use were <60 kg body weight (adjusted odds ratio [OR]: 0.310; confidence interval [CI]: 0.197-0.488) and CrCl <50 mL/min (adjusted OR: 0.629; CI: 0.404-0.980). There were 45 events (8.75%) of any bleeding, 9 (1.8%) of stroke/transient ischaemic attack (TIA) and four events (0.8%) of deep vein thrombosis (DVT)/pulmonary embolism (PE). However, there was no difference between the appropriately prescribed group (294 patients) and inappropriately prescribed group (220 patients) in the incidence of bleeding events (27 [9.2%] vs 18 [8.2%]), stroke/TIA (7 [2.4%] vs 2 [0.9%]) and DVT/PE (2 [0.7%] vs 2 [0.9%]), respectively.. Although edoxaban has a broad therapeutic window that does not require routine monitoring, it should be cautiously used in patients with renal insufficiency (CrCl <50 mL/min) and body weight <60 kg.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Pyridines; Renal Insufficiency; Republic of Korea; Retrospective Studies; Stroke; Thiazoles

Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) have substantially improved anticoagulation therapy for prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). The available routine care data have demonstrated the safety of different NOACs; however, such data for edoxaban are scarce. Here, we report baseline characteristics of 13,638 edoxaban-treated patients with AF enrolled between November 2016 and February 2018.. ETNA-AF-Europe is a multinational, multi-centre, post-authorisation, observational study conducted in 825 sites in 10 European countries. Patients will be followed up for four years.. Overall, 13,980 patients were enrolled of which 342 patients were excluded from the analysis. Mean patient age was 73.6 years with an average creatinine clearance of 69.4 mL/min. 56.6% were male. The calculated CHA. Edoxaban was predominantly initiated in older, often anticoagulation-naïve, unselected European patients with AF, with a good overall adherence to the approved label.. NCT02944019; Date of registration: October 24, 2016.

Topics: Administration, Oral; Aged; Aged, 80 and over; Atrial Fibrillation; Drug Labeling; Drug Utilization; Europe; Factor Xa Inhibitors; Female; Guideline Adherence; Hemorrhage; Humans; Male; Middle Aged; Practice Guidelines as Topic; Practice Patterns, Physicians'; Product Surveillance, Postmarketing; Pyridines; Registries; Risk Assessment; Risk Factors; Stroke; Thiazoles; Time Factors; Treatment Outcome

We investigated recurrent stroke volume with nonvalvular atrial fibrillation (NVAF) patients treated with non-vitamin K antagonist oral anticoagulants (NOACs) about clinical backgrounds and number of recurrent stroke.. We administered 4 NOACs, dabigatran, rivaroxaban, apixaban, and edoxaban in 101 postcardioembolic strokes with NVAF. In a retrospective study, we measured recurrent stroke volume with magnetic resonance imaging volumetric software and compared them between 10 vitamin K anticoagulant (VKA: warfarin) cases and 13 NOAC cases under anticoagulant therapy.. Of 101 cases, 31 were started with a VKA and switched to NOACs after 10 recurrent strokes. Other 70 cases were directly started with NOACs and 13 cases with NOACs as first anticoagulants had recurrent stroke. The frequency of recurrent stroke during anticoagulant therapy is not different between the VKA group and the 3 NOACs group. Recurrent stroke volume is significantly larger in the VKA group (26.4 cm. Secondary prevention with NOACs after stroke might be more beneficial than a VKA by reducing recurrent infarct volume.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Humans; Japan; Magnetic Resonance Imaging; Male; Pyrazoles; Pyridines; Pyridones; Recurrence; Retrospective Studies; Risk Factors; Rivaroxaban; Secondary Prevention; Stroke; Thiazoles; Time Factors; Treatment Outcome; Warfarin

To describe the early uptake of edoxaban; the fourth direct oral anticoagulant (DOAC) to enter the market.. Using the Danish nationwide health registries, we identified new users of edoxaban (n = 609) from June 6 (day of marketing) through June 2017. For comparison, we also identified new users of dabigatran (n = 2211), rivaroxaban (n = 19 227), and apixaban (n = 14 736). Users were described regarding indication of use, previous anticoagulant experience, comorbidity, and co-medication.. The rate of edoxaban initiation increased to 2.0 per 100 000 person months in June 2017, compared with 6.3, 37.5, and 27.0 for dabigatran, rivaroxaban, and apixaban. Atrial fibrillation was the most common registered indication for edoxaban (67%) as well as the other DOACs (41-55%). Overall, users of edoxaban were comparable to users of other DOACs (median age 75 vs 72-76 years and 57% vs 53-59% males), except for a generally lower concomitant use of other drugs. Noticeably, 95% of edoxaban users had previously received anticoagulant treatment compared with 31% to 43% for new users of other DOACs, with 77% switching directly from another anticoagulant treatment to edoxaban (45% directly from VKA and 32% directly from DOACs).. While the use of edoxaban is still limited compared with other DOACs, it is increasing. The majority of edoxaban users switch to edoxaban from other anticoagulant treatments. Continued monitoring of the utilization of DOACs, including effectiveness and safety, is considered essential to the safe and rational use of these drugs.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Denmark; Drug Utilization; Female; Humans; Male; Middle Aged; Product Surveillance, Postmarketing; Pyrazoles; Pyridines; Pyridones; Registries; Rivaroxaban; Stroke; Thiazoles

In recent years, direct oral anticoagulants (DOACs) have become an alternative to vitamin K antagonists (VKA) for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) as well as for prevention and treatment of deep venous thrombosis. Pivotal trials have demonstrated non-inferiority and potential superiority compared to warfarin, which increases the options of anticoagulant treatment. In our setting, the Anticoagulant Treatment Units (ATUs) and Primary Care Centres (PCCs) play an important role in the education, follow-up, adherence control and management in special situations of anticoagulated patients. These considerations have motivated us to elaborate the present consensus document that aims to establish clear recommendations that incorporate the findings of scientific research into clinical practice to improve the quality of care in the field of anticoagulation.. A group of experts from the Catalan Thrombosis Group (TROMBOC@T) reviewed all published literature from 2009 to 2016, in order to provide recommendations based on clinical evidence.. As a result of the project, a set of practical recommendations have been established that will facilitate treatment, education, follow-up and management in special situations of anticoagulated patients with ACODs.. Progressive increase in the use of DOACs calls for measures to establish and homogenise clinical management guidelines for patients anticoagulated with DOACs in ATUs and PCCs.

Topics: Administration, Oral; Age Factors; Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Embolism; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Warfarin

Topics: Atrial Fibrillation; Cost-Benefit Analysis; Factor Xa Inhibitors; Humans; Pulmonary Embolism; Pyridines; Stroke; Thiazoles; Treatment Outcome; Venous Thrombosis

Several studies have compared the cost effectiveness of non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin using results from clinical trials evaluating NOACs. However, the time in therapeutic range (TTR) of warfarin groups ranged across clinical trials, and all were below the therapeutic goal of 70%. We compared the cost effectiveness of edoxaban 60 mg, apixaban 5 mg, dabigatran 150 mg, dabigatran 110 mg, rivaroxaban 20 mg, and well-managed warfarin with a TTR of 70% in preventing stroke among patients with atrial fibrillation at high risk of bleeding.. For the six treatments, we used a Markov state-transition model to quantify lifetime costs in $US and effectiveness in quality-adjusted life-years (QALYs). We simulated relative risk ratios of clinical events with each NOAC versus warfarin with a TTR of 70% using published regression models that predict how the incidence of thrombotic or hemorrhagic events changes for each unit change in TTR. We re-ran our analysis for two other estimates of TTR: 65 and 75%.. Treatment with edoxaban 60 mg cost $US127,520/QALY gained compared with warfarin with a TTR of 70% and cost $US41,860/QALY gained compared with warfarin with a TTR of 65%. However, warfarin with a TTR of 75% was more effective and less expensive than all NOACs. For three levels of TTR, apixaban 5 mg, dabigatran 150 mg, dabigatran 110 mg, and rivaroxaban 20 mg were dominated strategies.. The comparative cost effectiveness of edoxaban and warfarin is highly sensitive to TTR. At the $US100,000/QALY willingness-to-pay threshold, our results suggest that warfarin is the most cost-effective treatment for patients who can achieve a TTR of 70%.

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Cost-Benefit Analysis; Dabigatran; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Hemorrhage; Humans; Markov Chains; Pyrazoles; Pyridines; Pyridones; Quality-Adjusted Life Years; Risk Adjustment; Rivaroxaban; Stroke; Therapeutic Equivalency; Thiazoles; Warfarin

Atrial fibrillation is the most common clinically relevant arrhythmia frequently causing systemic thromboembolic events. Traditionally vitamin K antagonists had been used for decades to prevent these events. The emerging of the new direct anticoagulants has revolutionized this treatment and a gradual growth and extensive spread of usage is expected. The latest one approved in Hungary, edoxaban, is a factor Xa inhibitor. Once-daily administration and favourable safety profile are major benefits of this drug. In a large clinical study with a high number of patients it proved to be at least as effective as warfarin in the prevention of stroke and systemic embolization while causing significantly less major bleedings. As the incidence of atrial fibrillation increases with age, the observation that, compared with the other direct oral anticoagulants, the administration of edoxaban in the elderly has a favourable net clinical benefit (in the rate of prevented thromboembolic events and the number of caused bleedings) may have a great importance. Orv Hetil. 2018; 159(20): 798-802.

Topics: Aged; Anticoagulants; Factor Xa Inhibitors; Female; Humans; Hungary; Male; Patient Safety; Pyridines; Stroke; Thiazoles; Thromboembolism; Treatment Outcome

Factor Xa inhibitors reduce stroke in patients with atrial fibrillation. Pulmonary veins (PVs) and the sinoatrial node (SAN) are crucial for genesis of atrial fibrillation. However, the electrophysiological effects of factor Xa inhibitors (edoxaban and rivaroxaban) on PVs and the SAN remain unclear. Conventional microelectrodes were used to record the action potential in isolated rabbit PVs and SAN preparations before and after administration of edoxaban (0.1, 0.3, and 1 μM) or rivaroxaban (0.01, 0.03, 0.1, and 0.3 μM). A whole-cell patch-clamp was used to record the late sodium current (I

Topics: Action Potentials; Animals; Atrial Fibrillation; Factor Xa Inhibitors; Guanidines; Male; Microelectrodes; Models, Animal; Myocytes, Cardiac; Oligopeptides; Patch-Clamp Techniques; Pulmonary Veins; Pyridines; Rabbits; Ranolazine; Receptor, PAR-1; Rivaroxaban; Sinoatrial Node; Sodium-Calcium Exchanger; Stroke; Thiazoles

It is unclear whether edoxaban shows better risk reduction of ischemic stroke, bleeding, and all-cause mortality than warfarin in Asian patients with nonvalvular atrial fibrillation (AF).. This study compared the effectiveness and safety of edoxaban with those of warfarin in a Korean population with AF.. Using the Korean National Health Insurance Service database, we included new users of edoxaban and warfarin in patients with AF from January 2014 to December 2016 (n = 4,200 on edoxaban, and n = 31,565 on warfarin) and analyzed the risk of ischemic stroke, intracranial hemorrhage (ICH), hospitalization for gastrointestinal (GI) bleeding, hospitalization for major bleeding, and all-cause death. The propensity score matching method was used to balance covariates across edoxaban and warfarin users.. We compared a 1:3 propensity score-matched cohort of patients with AF who were new users of edoxaban and warfarin (n = 4,061 and n = 12,183, respectively). Baseline characteristics were balanced between the 2 groups (median age 72 years; median CHA. In this real-world Asian population with AF, edoxaban might be associated with reduced risk of ischemic stroke, major bleeding, and all-cause death compared with warfarin. These benefits were consistent across various high-risk subgroups.

Topics: Aged; Aged, 80 and over; Asian People; Atrial Fibrillation; Cohort Studies; Factor Xa Inhibitors; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Mortality; National Health Programs; Pyridines; Republic of Korea; Stroke; Thiazoles; Treatment Outcome

Inappropriate doses of direct oral anticoagulants (DOACs) are often prescribed. This study evaluated the prevalence, outcomes, and predictors of the prescription of inappropriately low doses of 4 types of DOACs in patients with atrial fibrillation (AF).. We retrospectively analyzed prospectively collected data from a single-center registry with 2272 patients prescribed DOACs for AF (apixaban: 1014; edoxaban: 267; rivaroxaban: 498; dabigatran: 493). Patients were monitored for 2years and classified into appropriate-dose (n = 1,753; including appropriate low doses), inappropriate-low-dose (n = 490) and inappropriate-high-dose groups (n = 29). Major bleeding (MB) and thromboembolic events (TEEs) were evaluated.. In a single-center registry, 23% of patients with AF treated with a DOAC received an inappropriate dose. Several clinical factors, such as age and the creatinine clearance value, can identify patients at risk of under-treatment with DOACs.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Chi-Square Distribution; Dabigatran; Databases, Factual; Drug Dosage Calculations; Female; Hemorrhage; Humans; Inappropriate Prescribing; Incidence; Japan; Kaplan-Meier Estimate; Logistic Models; Male; Middle Aged; Odds Ratio; Prevalence; Pyrazoles; Pyridines; Pyridones; Registries; Retrospective Studies; Risk Factors; Rivaroxaban; Stroke; Thiazoles; Thromboembolism; Time Factors; Treatment Outcome

Patients with atrial fibrillation (AF) and advanced chronic kidney disease (CKD) are at high risk of adverse events and are complicated to manage. There is little evidence on the effects of non-vitamin K oral anticoagulants in patients with severe CKD. Preliminary data in patients taking edoxaban whose creatinine clearance fell below 30 mL/min showed a low risk of stroke and major bleeding. The aim of our study is to test the safety of edoxaban 30 mg/day in patients with severe renal impairment with an estimated glomerular filtration rate (eGFR) of 15-29 mL/min.. We analyzed retrospective data from 46 patients who had documented AF with severe renal impairment (eGFR between 15 and 29 mL/min). The follow-up, characterized by clinical examination and blood analysis, was performed at 3, 6, and 12 months. The main endpoint was the incidence of major bleedings or clinically relevant non-major (CRNM) bleedings or thromboembolic events.. At the time of the data collection, the average follow-up was 9.13 ± 3.0 months. There were no major bleedings, strokes, systemic embolisms, or cardiovascular deaths reported: one non-cardiac death and five minor hemorrhages occurred. No differences related to the severity of CKD were observed in the left ventricular ejection fraction at echocardiography and in the thrombotic and hemorrhagic risk profile.. In this explorative study analyzing patients with severe CKD treated with edoxaban 30 mg once daily, no major bleeding or thrombotic events were observed. Some minor bleedings were observed. While additional studies are necessary to confirm the results of this exploratory study, edoxaban 30 mg once daily appears to be safe in patients with severe CKD.

Topics: Aged; Aged, 80 and over; Factor Xa Inhibitors; Female; Follow-Up Studies; Glomerular Filtration Rate; Hemorrhage; Humans; Male; Pyridines; Registries; Renal Insufficiency, Chronic; Retrospective Studies; Severity of Illness Index; Stroke; Thiazoles

Advances in cancer therapy have led to a significant improvement of survival in most types of malignancies over the past few decades. As a result, there is a growing population of cancer survivors, expected to reach 18 million people in 2030 in the US and a similar number in Europe. Interestingly, cancer survivor studies have shown that although about half of these patients eventually die of cancer, one third of them actually die of cardiovascular disease. Arrhythmias represent a significant part of cardiovascular complications and atrial fibrillation is the main arrhythmia occurring in cancer patients.Antithrombotic therapy is a challenge: the optimal international normalized ratio (INR) level in patients on therapy with vitamin K antagonists is achieved in only 12% of them; in these patients, direct oral anticoagulants seem to be effective and safe for the prevention of stroke and systemic embolic events compared to warfarin and have similar risk of major bleeding. Among the trials, ENGAGE AF-TIMI 48 provides more data on the efficacy and safety of edoxaban in cancer patients.

Topics: Anticoagulants; Atrial Fibrillation; Cancer Survivors; Cardiovascular Diseases; Embolism; Factor Xa Inhibitors; Hemorrhage; Humans; International Normalized Ratio; Neoplasms; Pyridines; Stroke; Thiazoles; Warfarin

Background and Purpose- The purpose of this study was to investigate the impact of improved antithrombotic treatment in atrial fibrillation after the introduction of non-vitamin K antagonist oral anticoagulants on the incidence of stroke and bleeding in a real-life total population, including both primary and secondary care. Methods- All resident and alive patients with a recorded diagnosis for atrial fibrillation during the preceding 5 years in the Stockholm County Healthcare database (Vårdanalysdatabasen) were followed for clinical outcomes during 2012 (n=41 008) and 2017 (n=49 510). Results- Pharmacy claims for oral anticoagulants increased from 51.6% to 73.8% (78.7% among those with CHA

Topics: Administration, Oral; Adult; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Cohort Studies; Dabigatran; Female; Hemorrhage; Humans; Incidence; Male; Middle Aged; Practice Guidelines as Topic; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Thiazoles; Warfarin

Background and Purpose- Edoxaban is a direct oral factor Xa inhibitor with proven efficacy and safety among patients with atrial fibrillation. Concerns have been raised about an excess of stroke among patients with creatinine clearance (CrCl) >95 mg/mL treated with edoxaban. We assessed the real-world effectiveness and safety of edoxaban in atrial fibrillation patients in relation to CrCl. Methods- In the Korean National Health Insurance Service data during the period from January to December 2016, we identified 9537 edoxaban-treated patients. Effectiveness and safety outcomes were compared between high-dose edoxaban regimen (HDER, 60 mg daily, n=2840) and a propensity score-matched warfarin group (n=2840) and between low-dose edoxaban regimen (LDER, 30 mg daily, n=3016) and matched warfarin group (n=3016). Results- The median follow-up period was 5.0 months (interquartile range, 2-7 months). The mean age was 68 years, and 63% were men in HDER group, and the mean age was 73 years, and 52% were men in LDER group. Compared with warfarin, both HDER and LDER significantly decreased the risk for ischemic stroke or systemic embolism (S/SE; HDER: adjusted hazard ratio [aHR], 0.44; 95% CI, 0.31-0.64; LDER: aHR, 0.57; 95% CI, 0.42-0.78), major bleeding (HDER: aHR, 0.40; 95% CI, 0.26-0.61; LDER: aHR, 0.61; 95% CI, 0.43-0.85), and mortality (HDER: aHR, 0.34; 95% CI, 0.22-0.53; LDER: aHR, 0.55; 95% CI, 0.41-0.73). In patients with CrCl >95 mL/min, the incidence of S/SE was higher with LDER than warfarin and comparable between HDER and warfarin group. There was lower effectiveness for the prevention of S/SE with LDER compared with warfarin at higher CrCl levels ( P for interaction=0.023). Conclusions- In real-world practice, both doses of edoxaban were associated with reduced risks for S/SE, major bleeding, and mortality compared with warfarin. LDER had lower effectiveness for the prevention of S/SE compared with warfarin at higher levels of CrCl (>95 mL/min).

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Embolism; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Pyridines; Stroke; Thiazoles; Warfarin

Background Anticoagulation in patients with malignancy and atrial fibrillation is challenging because of enhanced risks for thrombosis and bleeding and the frequent need for invasive procedures. Data on direct oral antagonists in such patients are sparse. Methods and Results The ENGAGE AF - TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction Study 48) trial randomized 21 105 patients with atrial fibrillation to edoxaban or warfarin. Patients with malignancy, defined as a postrandomization new diagnosis or recurrence of remote cancer, were followed up over a median of 2.8 years. Adjusted Cox proportional hazard models were used to evaluate the safety and efficacy of edoxaban versus warfarin. Over a median of 495 days (interquartile range, 230-771 days), 1153 patients (5.5%) were diagnosed with new or recurrent malignancy, most commonly involving the gastrointestinal tract (20.6%), prostate (13.6%), and lung (11.1%). Malignancy was associated with increased risk of death (adjusted hazard ratio [HR], 3.12; 95% confidence interval [CI], 2.78-3.50) and major bleeding (adjusted HR, 2.45; 95% CI, 2.07-2.89), but not stroke/systemic embolism (adjusted HR, 1.08; 95% CI, 0.83-1.42). Relative outcomes with higher-dose edoxaban versus warfarin were consistent regardless of malignancy status for stroke/systemic embolism ( HR , 0.60 [95% CI, 0.31-1.15] for malignancy versus HR , 0.89 [95% CI, 0.76-1.05] for no malignancy; interaction P=0.25) and major bleeding ( HR , 0.98 [95% CI, 0.69-1.40] for malignancy versus HR , 0.79 [95% CI, 0.69-1.05] for no malignancy; interaction P=0.31). There was, however, a significant treatment interaction for the composite ischemic end point (ischemic stroke/systemic embolism/myocardial infarction), with greater efficacy of higher-dose edoxaban versus warfarin in patients with malignancy ( HR , 0.54; 95% CI, 0.31-0.93) compared with no malignancy ( HR , 1.02; 95% CI, 0.88-1.18; interaction P=0.026). Conclusions In patients with atrial fibrillation who develop malignancy, the efficacy and safety profile of edoxaban relative to warfarin is preserved, and it may represent a more practical alternative.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Comorbidity; Embolism; Factor Xa Inhibitors; Female; Gastrointestinal Neoplasms; Hemorrhage; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Proportional Hazards Models; Prostatic Neoplasms; Pyridines; Stroke; Thiazoles; Warfarin

Background The aims of the present study were to investigate the relationships between prior direct oral anticoagulant ( DOAC ) therapy and infarct volume and the site of arterial occlusion in patients with acute ischemic stroke and non-valvular atrial fibrillation. Methods and Results From March 2011 through November 2016, consecutive patients with acute ischemic stroke in the middle cerebral artery territory and non-valvular atrial fibrillation were recruited. The infarct volume was assessed semi-automatically using initial diffusion-weighted imaging, and the arterial occlusion site was evaluated on magnetic resonance angiography. The effect of prior DOAC treatment on the site of arterial occlusion was assessed by multivariate ordinal logistic regression analysis. A total of 330 patients (149 women; median age 79 [quartiles 71-86] years; median National Institutes of Health Stroke Scale score 11 [4-21]) were enrolled. Of these, 239 were on no anticoagulant, 40 were undertreated with a vitamin K antagonist ( VKA ), 22 were sufficiently treated with VKA ( PT - INR ≥1.6), and 29 were on a DOAC before the acute ischemic stroke. The infarct volume on admission differed among the groups (median 14.5 [2.0-59.8] cm

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cerebral Angiography; Dabigatran; Diffusion Magnetic Resonance Imaging; Female; Humans; Infarction, Middle Cerebral Artery; International Normalized Ratio; Logistic Models; Magnetic Resonance Angiography; Male; Multivariate Analysis; Prothrombin Time; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Severity of Illness Index; Stroke; Thiazoles; Warfarin

Background Patients with impaired liver function ( ILF ) were excluded from clinical trials that investigated non-vitamin K antagonist oral anticoagulants ( NOAC s) for stroke prevention in patients with atrial fibrillation. The aim of this study was to evaluate the efficacy and safety of NOAC s in atrial fibrillation patients with ILF . Methods and Results A cohort study based on electronic medical records was conducted from 2009 to 2016 at a multicenter healthcare provider in Taiwan and included 6451 anticoagulated atrial fibrillation patients (aged 76.7±7.0 years, 52.5% male). Patients were classified into 2 subgroups: patients with normal liver function (n=5818) and patients with ILF (n=633, 9.8%). Cox regression analysis was performed to investigate the risks of thromboembolism, bleeding, and death associated with use of NOAC s and warfarin in patients with normal liver function and ILF , respectively. In patients with normal liver function, compared with warfarin therapy (n=2928), NOAC therapy (n=4048) was associated with significantly lower risks of stroke or systemic embolism (adjusted hazard ratio: 0.75; 95% confidence interval, 0.65-0.88; P<0.001) and death (adjusted hazard ratio: 0.69; 95% confidence interval, 0.60-0.80; P<0.001) with no difference in major bleeding or gastrointestinal bleeding. In patients with ILF , compared with warfarin therapy (n=394), NOAC therapy (n=342) was associated with significantly lower risk of death (adjusted hazard ratio: 0.64; 95% confidence interval, 0.49-0.83; P<0.001), but no difference in stroke or systemic embolism, major bleeding, or gastrointestinal bleeding. Conclusions In atrial fibrillation patients with ILF , NOAC therapy and warfarin therapy were associated with similar risks of stroke or systemic embolism, major bleeding, and gastrointestinal bleeding.

Topics: Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Cohort Studies; Dabigatran; Factor Xa Inhibitors; Female; Gastrointestinal Hemorrhage; Hemorrhage; Hepatic Insufficiency; Humans; Male; Proportional Hazards Models; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Thiazoles; Thromboembolism; Warfarin

New oral anticoagulants (NOAC) have been introduced in Swedish health care as first line treatment of atrial fibrillation and venous thromboembolism. NOAC have also been studied in combination with platelet antiaggregation in both patients with coronary and peripheral arterial disease, and reduced doses will presumably emerge as routine treatment also in these conditions.

Topics: Acute Coronary Syndrome; Anticoagulants; Antithrombins; Cardiovascular Diseases; Coronary Artery Disease; Dabigatran; Drug Therapy, Combination; Factor Xa Inhibitors; Humans; Myocardial Infarction; Myocardial Ischemia; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Sweden; Thiazoles

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Factor Xa Inhibitors; Humans; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiazoles; Warfarin

Background and Purpose- The increased use of novel oral anticoagulants (NOACs) to control atrial fibrillation is largely driven by the assumption that they are equally effective as warfarin at preventing ischemic stroke while putting patients at lower risk of hemorrhages. To test this hypothesis, a retrospective study of the relative incidence of strokes among patients taking NOACs versus those taking warfarin is performed. Methods- Relative stroke incidence in the 2 groups of patients was compared using odds ratios and Fisher exact tests for significance using a data set of 71 365 on NOACs and 59 546 patients on warfarin. In addition, the 7033 patients with a record of both warfarin and NOAC use were analyzed as a separate cohort. Results- There is a significantly higher (odds ratio=1.29, <0.001) frequency of ischemic strokes among patients prescribed NOACs compared with those on warfarin. The relative frequency of ischemic strokes was also higher for every individual NOAC compared with warfarin (these higher frequencies are statistically significant for dabigatran and apixaban, though not for edoxaban and rivaroxaban). There is a lower incidence of intracranial hemorrhages and nontraumatic hemorrhages in general among patients taking NOACs, consistent with the published literature. Comparisons of the demographic and clinical profiles of the patients taking NOACs to those on warfarin do not show significantly higher background stroke risk in NOAC patients; in fact, patients on NOACs tend to be at lower background risk overall for ischemic strokes. Conclusions- Because NOAC use is associated with higher ischemic stroke risk together with a lower risk of hemorrhages than warfarin use, it can be concluded that patients on warfarin are more strongly anticoagulated. The observed effect could be a secondary consequence of dosage control or alternatively a result of different anticoagulant effects among the different medications.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Cohort Studies; Dabigatran; Female; Humans; Incidence; Intracranial Hemorrhages; Male; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Thiazoles; Warfarin

Background and Purpose- Direct oral anticoagulants (DOACs) are safer, at least equally efficacious, and cost-effective compared to warfarin for stroke prevention in atrial fibrillation (AF) but they remain underused, particularly in demented patients. We estimated the cost-effectiveness of DOACs compared with warfarin in patients with AF and Alzheimer's disease (AD). Methods- We constructed a microsimulation model to estimate the lifetime costs, quality-adjusted life-years (QALYs), and cost-effectiveness of anticoagulation therapy (adjusted-dose warfarin and various DOACs) in 70-year-old patients with AF and AD from a US societal perspective. We stratified patient cohorts based on stage of AD and care setting. Model parameters were estimated from secondary sources. Health benefits were measured in the number of acute health events, life-years, and QALYs gained. We classified alternatives as cost-effective using a willingness-to-pay threshold of $100 000 per QALY gained. Results- For patients with AF and AD, compared with warfarin, DOACs increase costs but also increase QALYs by reducing the risk of stroke. For mild-AD patients living in the community, edoxaban increased lifetime costs by $6603 and increased QALYs by 0.076 compared to warfarin, yielding an incremental cost-effectiveness ratio of $86 882/QALY gained. Even though DOACs increased QALYs compared with warfarin for all patient groups (ranging from 0.019 to 0.085 additional QALYs), no DOAC treatment alternative had an incremental cost-effectiveness ratio <$150 000/QALY gained for patients with moderate to severe AD. For patients living in a long-term care facility with mild AD, the DOAC with the lowest incremental cost-effectiveness ratio (rivaroxaban) costs $150 169 per QALY gained; for patients with more severe AD, the incremental cost-effectiveness ratios were higher. Conclusions- For patients with AF and mild AD living in the community, edoxaban is cost-effective compared with warfarin. Even though patients with moderate and severe AD living in the community and patients with any stage of AD living in a long-term care setting may obtain positive clinical benefits from anticoagulation treatment, DOACs are not cost-effective compared with warfarin for these populations. Compared to aspirin, no oral anticoagulation (warfarin or any DOAC) is cost effective in patients with AF and AD.

Topics: Aged; Alzheimer Disease; Anticoagulants; Atrial Fibrillation; Cost-Benefit Analysis; Dabigatran; Disease Progression; Health Care Costs; Humans; Pyrazoles; Pyridines; Pyridones; Quality-Adjusted Life Years; Rivaroxaban; Stroke; Thiazoles; Warfarin

Data evaluating the impact of the periprocedural administration of novel oral anticoagulants (NOACs) on complications in the setting of pulmonary vein (PV) isolation using cryoballoon (CB) is limited. In the present study, our aim was to analyze procedural characteristics and incidence of complications in those patients who underwent CB ablation for atrial fibrillation and the impact of NOACs on adverse events compared with vitamin K antagonists (VKAs). Consecutive patients with drug resistant atrial fibrillation who underwent PV isolation by CB as index procedure were retrospectively included in our analysis. In group I, 290 of 454 patients (63.9%) received VKAs (warfarin: n = 222 and acenocoumarol: n = 68), and in group II, 164 of 454 patients (36.1%) were treated with NOACs (rivaroxaban: n = 71; dabigatran: n = 60; and apixaban: n = 33). Age was significantly higher in the group II (62.8 ± 9.7 vs 58.6 ± 11.3; p <0.001). During the study period, 454 consecutive patients (male 71%, age 60.1 ± 10.9 years) were enrolled. Major complications occurred in 9 patients (2.0%): peripheral vascular complications were observed in 6 patients (1.3% per procedure), persistent phrenic nerve palsy occurred in 2 (0.4%), and transient ischemic attacks in 1 (0.2%). In both groups, the incidence of major complications was similar (group I [VKAs]: 7 patients [2.4%] vs group II [NOACs]: 2 patients [1.2%]; p = 0.5). In conclusion, CB ablation is a safe procedure for PV isolation and is associated with low complication rates. The incidence of adverse events in PV isolation using the second-generation CB with the periprocedural administration of NOACs is not significantly different than VKA treatment.

Topics: Ablation Techniques; Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Belgium; Cryosurgery; Dabigatran; Dose-Response Relationship, Drug; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Follow-Up Studies; Humans; Incidence; Intraoperative Period; Italy; Male; Middle Aged; Postoperative Complications; Prognosis; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Survival Rate; Thiazoles; Time Factors; Vitamin K

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Craniocerebral Trauma; Dabigatran; Gastrointestinal Hemorrhage; Humans; Intracranial Hemorrhages; Pyrazoles; Pyridines; Pyridones; Stroke; Thiazoles; Warfarin

For patients with atrial fibrillation, non-vitamin K oral anticoagulants, or NOACs (dabigatran, rivaroxaban, edoxaban, and apixaban) have been proven non-inferior or superior to warfarin in preventing stroke and systemic embolism, and in risk of haemorrhage. In the pivotal NOAC studies, quality of warfarin treatment was poor with mean time in therapeutic range (TTR) 55-65%, compared with ≥70% in Swedish clinical practice.. We compared NOACs (as a group) to warfarin in non-valvular atrial fibrillation, studying all 12,694 patients starting NOAC treatment within the Swedish clinical register and dosing system Auricula, from July 1, 2011 to December 31, 2014, and matching them to 36,317 patients starting warfarin using propensity scoring. Endpoints were thromboembolic events and major bleedings that were fatal or required hospital care. Outcome data were collected from validated Swedish hospital administrative and clinical registers.. Mean age was 72.2 vs 72.3 years, proportion of males 58.2% vs 57.0%, and mean follow-up time 299 vs 283 days for NOACs and warfarin. Distribution of NOACs was: dabigatran 40.3%, rivaroxaban 31.2%, and apixaban 28.5%. Mean TTR was 70%. There were no significant differences in rates of thromboembolic/thrombotic events or gastrointestinal bleeding. NOAC treated patients had lower rates of major bleeding overall, hazard ratio 0.78 (95% confidence interval 0.67-0.92), intracranial bleeding 0.59 (0.40-0.87), haemorrhagic stroke 0.49 (0.28-0.86), and other major bleeding 0.71 (0.57-0.89).. For patients with atrial fibrillation, NOACs are as effective for stroke prevention as well-managed warfarin but cause fewer major bleedings.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Hemorrhage; Humans; Male; Middle Aged; Proportional Hazards Models; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Thiazoles; Warfarin

Topics: Administration, Oral; Anticoagulants; Aspirin; Atrial Fibrillation; Clinical Trials, Phase III as Topic; Dabigatran; Humans; Intracranial Hemorrhages; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Vitamin K; Warfarin

Stroke risk may be more than 3-fold higher among patients with chronic kidney disease stage 5D (CKD-5D) compared to the general population, with the highest stroke rates noted among those 85 years and older. Atrial fibrillation (AF), a strong risk factor for stroke, is the most common arrhythmia and affects >7% of the population with CKD-5D. Warfarin use is widely acknowledged as an important intervention for stroke prevention with nonvalvular AF in the general population. However, use of oral anticoagulants for stroke prevention in patients with CKD-5D and nonvalvular AF continues to be debated by the nephrology community. In this National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) controversies report, we discuss the existing observational studies that examine warfarin use and associated stroke and bleeding risks in adults with CKD-5D and AF. Non-vitamin K-dependent oral anticoagulants and their potential use for stroke prevention in patients with CKD-5D and nonvalvular AF are also discussed. Data from randomized clinical trials are urgently needed to determine the benefits and risks of oral anticoagulant use for stroke prevention in the setting of AF among patients with CKD-5D.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Hemorrhage; Humans; Kidney Failure, Chronic; Practice Guidelines as Topic; Pyrazoles; Pyridines; Pyridones; Renal Dialysis; Rivaroxaban; Stroke; Thiazoles; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Chemical and Drug Induced Liver Injury; Factor Xa Inhibitors; Hemorrhage; Humans; International Normalized Ratio; Pulmonary Embolism; Pyridines; Stroke; Thiazoles; Venous Thrombosis; Warfarin

The comparative cost-effectiveness of all oral anticoagulants approved up to date has not been evaluated from the US perspective. The objective of this study was to compare the cost-effectiveness of edoxaban 60mg, apixaban 5mg, dabigatran 150mg, dabigatran 110mg, rivaroxaban 20mg and warfarin in stroke prevention in atrial fibrillation patients at high-risk of bleeding (defined as HAS-BLED score≥3).. We constructed a Markov state-transition model to evaluate lifetime costs and quality-adjusted life years (QALYs) with each of the six treatments from the perspective of US third-party payers. Probabilities of clinical events were obtained from the RE-LY, ROCKET-AF, ARISTOTLE and ENGAGE AF-TIMI trials; costs were derived from the Healthcare Cost and Utilization Project, and other studies. Because edoxaban is only indicated in patients with creatinine clearance ≤95ml/min, we re-ran our analyses after excluding edoxaban from the analysis.. Treatment with edoxaban 60mg cost $77,565/QALY gained compared to warfarin, and apixaban 5mg cost $108,631/QALY gained compared to edoxaban 60mg. When edoxaban was not included in the analysis, treatment with apixaban 5mg cost $84,128/QALY gained, compared to warfarin. Dabigatran 150mg, dabigatran 110mg and rivaroxaban 20mg were dominated strategies.. For patients with creatinine clearance between 50 and 95ml/min, apixaban 5mg was the most cost-effective treatment for willingness-to-pay thresholds (WTP) above $115,000/QALY gained, and edoxaban 60mg was cost-effective when the WTP was between $75,000 and $115,000/QALY gained. For patients with creatinine clearance >95ml/min, apixaban 5mg was the most cost-effective treatment for WTP thresholds above $80,000/QALY gained.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cost-Benefit Analysis; Dabigatran; Hemorrhage; Humans; Markov Chains; Pyrazoles; Pyridines; Pyridones; Quality-Adjusted Life Years; Rivaroxaban; Stroke; Thiazoles; Warfarin

The safety and efficacy of the contemporary atrial fibrillation (AF) ablation in patients with a recent or previous history of cardioembolic stroke (CS) or transient ischemic attack (TIA) remain to be established.. A total of 447 patients who underwent first-ever contact force (CF)-guided AF ablation with circumferential pulmonary vein isolation were included. Of these, 17 had CS or TIA within 6 months before ablation (Group 1), 30 more than 6 months before ablation (Group 2), and the other 400 without CS or TIA (Group 3). Procedural complications and recurrence of AF and atrial tachyarrhythmias were compared among the 3 groups.. The mean age was 71±7, 66±9, and 61±11 years in Groups 1, 2, and 3, respectively (p<0.05, Group 1 versus Group 3). The oral anticoagulants were warfarin (n=108, 24.1%), dabigatran (n=101, 22.6%), rivaroxaban (n=147, 32.9%), apixaban (n=87, 19.5%), and edoxaban (n=4, 0.9%), and did not differ among the 3 groups. Median follow-up period was 14 [IQR 12-22], 13 [12-14], and 12 [10-16] months, respectively. One episode of cardiac tamponade, 2 episodes of arteriovenous fistula, and some minor complications occurred in Group 3, but no complications occurred in Groups 1 and 2 in the periprocedural period. Although one episode of CS occurred 11 days after the procedure in Group 3, there were no periprocedural CS, TIA, or major bleedings in Groups 1 and 2. AF recurrence-free rate after the procedure was 76.5%, 86.7%, and 79.1% in Groups 1, 2, and 3, respectively, and there was no difference in Kaplan-Meier curves among the 3 groups.. The safety and efficacy of CF-guided AF ablation in the era of direct oral anticoagulants in patients with a recent or previous history of CS or TIA are similar to those in patients without it.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Catheter Ablation; Dabigatran; Female; Hemorrhage; Humans; Ischemic Attack, Transient; Male; Middle Aged; Pulmonary Veins; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Treatment Outcome; Warfarin

For nonvalvular atrial fibrillation (NVAF), novel oral anticoagulants (NOACs) have been found noninferior to warfarin for stroke/systemic embolization prevention, and major bleeding events. Recent meta-analysis of NOACs versus warfarin in atrial fibrillation (AF) showed that women on warfarin have greater risk of stroke/embolism than men, and when both are treated with NOACs, differences disappear.. NOACs differ in pharmacologic properties, thus they may differ from one another in their effects on women with AF. Using dose-adjusted warfarin as the common comparator, an indirect comparison of rivaroxaban, apixaban, dabigatran 110 and 150 mg, and edoxaban 30 and 60 mg for efficacy (stroke/embolism prevention) and safety (major bleeding events) in women with AF was performed. Data from ROCKET-AF, RE-LY, ENGAGE AF TIMI, and ARISTOTLE were analyzed and compared according to the Bucher method.. No significant difference was found for any NOAC compared with alternatives in safety or efficacy for women with AF. Examination of odds ratio comparisons alone showed possible favorable efficacy in dabigatran 150 mg, and unfavorable efficacy with favorable safety in edoxaban 30 mg.. NOACs may slightly differ in their effect in women; the potential differences are very small and likely clinically negligible. Thus, NOACs can be used interchangeably in women according to patient and physician preferences to increase adherence.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Hemorrhage; Humans; Odds Ratio; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiazoles; Treatment Outcome; Warfarin

The direct oral anticoagulants (DOACs) are drugs used in clinical practice since 2009 for the prevention of stroke or systemic embolism in non-valvular atrial fibrillation, and for the treatment and secondary prevention of venous thromboembolism. The four DOACs, including the three factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) and one direct thrombin inhibitor (dabigatran) provide oral anticoagulation therapy alternatives to Vitamin K antagonists (VKAs). Despite their clear advantages, the DOACs require on the part of the internist a thorough knowledge of their pharmacokinetic and pharmacodynamic characteristics to ensure their correct use, laboratory monitoring and the appropriate management of adverse events. This document represents a consensus paper on the use of DOACs by representatives of three Italian scientific societies: the Italian Society of Internal Medicine (SIMI), the Federation of the Associations of Hospital Managers (FADOI), and the Society for the Study of Haemostasis and Thrombosis (SISET). This document formulates expert opinion guidance for pragmatic managing, monitoring and reversing the anticoagulant effect of DOACs in both chronic and emergency settings. This practical guidance may help the internist to create adequate protocols for patients hospitalized ion internal medicine wards, where patients are often elderly subjects affected by poly-morbidities and renal insufficiency, and, thus, require particular attention to drug-drug interactions and peri-procedural protocols.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Clinical Competence; Consensus; Dabigatran; Drug-Related Side Effects and Adverse Reactions; Factor Xa Inhibitors; Food-Drug Interactions; Humans; Internal Medicine; Italy; Liver Diseases; Perioperative Period; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Time Factors; Venous Thromboembolism

To estimate the quality-adjusted life-years (QALYs), costs, and cost-effectiveness of high-dose edoxaban compared with adjusted-dose warfarin in patients at risk for stroke who have nonvalvular atrial fibrillation (NVAF) and a creatinine clearance (Clcr ) of 15-95 ml/minute.. A Markov model was created to compare the cost-effectiveness of high-dose edoxaban and adjusted-dose warfarin in patients with a Clcr of 15-95 ml/minute. The model was performed from a U.S. societal perspective and assumed patients initiated therapy at 70 years of age, had a mean CHADS2 (congestive heart failure, hypertension, age 75 or older, diabetes, stroke) score of 3, and no contraindications to anticoagulation. The model assumed a cycle length of 1 month and a lifetime horizon (maximum of 30 years/360 cycles). Data sources included renal subgroup analysis of the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation (ENGAGE-AF) trial and other published studies. Outcomes included lifetime costs (2014 US$), QALYs, and incremental cost-effectiveness ratios. The robustness of the model's conclusions was tested using one-way and 10,000-iteration probabilistic sensitivity analysis (PSA).. Patients treated with high-dose edoxaban lived an average of 10.50 QALYs at a lifetime treatment cost of $99,833 compared with 10.11 QALYs and $123,516 for those treated with adjusted-dose warfarin. The model's conclusions were found to be robust upon one-way sensitivity analyses. PSA suggested high-dose edoxaban was economically dominant compared with adjusted-dose warfarin in more than 99% of the 10,000 iterations run.. High-dose edoxaban appears to be an economically dominant strategy when compared with adjusted-dose warfarin for the prevention of stroke in NVAF patients with a Clcr of 15-95 ml/minute and an appreciable risk of stroke.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Cost-Benefit Analysis; Female; Health Care Costs; Humans; Male; Markov Chains; Pyridines; Quality-Adjusted Life Years; Stroke; Thiazoles; Warfarin

The objective of the study is to compare the cost-effectiveness of oral anticoagulants among atrial fibrillation patients at an increased stroke risk.. A Markov model was constructed to project the lifetime costs and quality-adjusted survival (QALYs) of oral anticoagulants using a private payer's perspective. The distribution of stroke risk (CHADS2 score: congestive heart failure, hypertension, advanced age, diabetes mellitus, stroke) and age of the modeled population was derived from a cohort of commercially insured patients with new-onset atrial fibrillation. Probabilities of treatment specific events were derived from published clinical trials. Event and downstream costs were determined from the cost of illness studies. Drug costs were obtained from 2015 National Average Drug Acquisition Cost data.. In the base case analysis, warfarin was the least costly ($46 241; 95% CI, 44 499-47 874) and apixaban had the highest QALYs (9.38; 95% CI, 9.24-9.48 QALYs). Apixaban was found to be a cost-effective strategy over warfarin (incremental cost-effectiveness ratio=$25 816) and dominated other anticoagulants. Probabilistic sensitivity analysis showed that apixaban had at least a 61% chance of being the most cost-effective strategy at willingness to pay value of $100 000 per QALY. Among patients with CHADS2 ≥3, dabigatran was the dominant strategy. The model was sensitive to efficacy estimates of apixaban, dabigatran, and edoxaban and the cost of these drugs.. All the newer oral anticoagulants compared were more effective than adjusted dosed warfarin. Our model showed that apixaban was the most effective anticoagulant in a general atrial fibrillation population and has an incremental cost-effectiveness ratio <$50 000/QALY. For those with higher stroke risk (CHADS2≥3), dabigatran was the most cost-effective treatment option.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Cost-Benefit Analysis; Dabigatran; Humans; Insurance, Health; Middle Aged; Models, Theoretical; Pyrazoles; Pyridines; Pyridones; Quality-Adjusted Life Years; Risk; Rivaroxaban; Severity of Illness Index; Stroke; Thiazoles; Warfarin

Topics: Administration, Oral; Aged, 80 and over; Anticoagulants; Brain; Cerebral Hemorrhage; Drug Therapy, Combination; Female; Humans; Pyridines; Recurrence; Stroke; Thiazoles; Thrombolytic Therapy

Here we report first 2 cases of patients with nonvalvular atrial fibrillation with acute cardioembolic stroke in whom thrombi in the left atrial appendage (LAA) were resolved by edoxaban administration. Case 1 reports an 86-year-old woman who suddenly showed right hemiparesis and aphasia due to occlusion of the left middle cerebral artery. She received mechanical thrombectomy and recovered neurologically. Transesophageal echocardiography (TEE) performed on day 1 demonstrated thrombus in the LAA. The thrombus was resolved on day 13 after initiation of edoxaban (30 mg once daily) instead of warfarin, which was administered before stroke onset. Case 2 reports a 49-year-old man who was admitted because of the sudden onset of left hemiparesis and aphasia. TEE demonstrated thrombus in the LAA on day 4, and edoxaban therapy (60 mg once daily) was initiated. The thrombus resolution was observed on day 16, and no embolic stroke occurred.

Topics: Aged, 80 and over; Angiography, Digital Subtraction; Atrial Appendage; Atrial Fibrillation; Brain Ischemia; Cerebral Angiography; Echocardiography, Transesophageal; Factor Xa Inhibitors; Female; Humans; Magnetic Resonance Angiography; Male; Middle Aged; Pyridines; Stroke; Thiazoles; Thrombectomy; Thrombosis; Time Factors; Treatment Outcome

The non-vitamin K antagonist oral anticoagulants (NOACs) have varying degrees of renal elimination which may be challenging in patients with heart failure (HF) and atrial fibrillation (AF). We examined the severity and variation in renal impairment, and the proportion of patients requiring NOAC cessation or dose reduction.. A retrospective analysis of patients with HF and AF in the Candesartan in Heart failure Assessment of Reduction in Mortality and Morbidity programme was carried out. Trends in renal impairment over 26 months were defined using Cockcroft-Gault (CG), simplified Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. Mean estimated glomerular filtration rate (eGFR) was worse at every time point in patients with AF compared with those without AF, the difference being ∼11 mL/min (CG), 9 mL/min (CKD-EPI), and 7 mL/min (MDRD). As renal function declined, CG classified a greater proportion of patients as having moderate or severe CKD and agreement with MDRD/CKD-EPI declined. At least moderate renal impairment was present in a quarter of patients with AF at baseline, a third by study completion, and approaching a half at least once during follow-up. The projected need for NOAC dose reduction was accordingly high, though it varied between individual NOACs due to different criteria for adjustment.. Renal impairment in patients with HF and AF is common, fluctuates, progresses, and frequently mandates NOAC dose reduction, though the need for cessation is rare. Baseline renal function, the method of estimating GFR, and intensity of monitoring should be considered when commencing oral anticoagulation.

Topics: Aged; Antithrombins; Atrial Fibrillation; Dabigatran; Factor Xa Inhibitors; Female; Glomerular Filtration Rate; Heart Failure; Humans; Male; Middle Aged; Pyrazoles; Pyridines; Pyridones; Renal Insufficiency, Chronic; Rivaroxaban; Severity of Illness Index; Stroke; Thiazoles

Topics: Humans; Pyridines; Stroke; Thiazoles; Warfarin

In the coming decades, the number of Europeans with atrial fibrillation (AF) is set to rise as the population ages, and so with it will the number of strokes. The risk of thromboembolism (principally stroke and systemic embolism) and death can be reduced by the use of the vitamin K antagonists (VKA, e.g. warfarin) and more so by non-VKA oral anticoagulants (NOACs) such as edoxaban.. We modelled the effect of the increasing use of edoxaban in preference to warfarin in a European AF population from both clinical and economic perspectives. We estimate that the introduction of NOACs in 2010 eliminated over 88 000 thromboembolisms and deaths annually, of which over 17 000 were ischaemic strokes. At a 1-year cost of €30k per ischaemic stroke, this strategy saved €510 million annually. Should the use of edoxaban increase from 11% in 2013 to 75% by 2030, we expect that rate of thromboembolism and death will fall from 5.67 to 5.42 total events per million patients per year, which will further eliminate over 12 000 of these events annually. At an inflation-adjusted 1-year cost of approximately €35k per ischaemic stroke, this will save €44.5 million each year. At a conservative rate of increase in the AF population of 2.2-fold from 2005, in 2050 there will be around 180 000 AF-related ischaemic strokes that, at an inflation-adjusted cost of around €62k per stroke, sums to €11 116 million. Should the rate of AF rise 2.6-fold from 2005, then in 2050 there will be 214 500 ischaemic strokes that will cost around €13 300 million.. Our data point to a substantial increase in the human and economic cost burden of AF and so emphasize the need to reduce this burden. This may be achieved by the increased use of oral anticoagulants, particularly with the NOACs such as edoxaban.

Topics: Administration, Oral; Atrial Fibrillation; Cost Savings; Cost-Benefit Analysis; Drug Costs; Europe; Factor Xa Inhibitors; Forecasting; Humans; Models, Economic; Practice Patterns, Physicians'; Pyridines; Stroke; Thiazoles; Thromboembolism; Time Factors; Treatment Outcome; Warfarin

Non-vitamin K antagonist oral anticoagulants (NOACs, dabigatran, rivaroxaban, apixaban, and edoxaban) have been increasingly used as alternatives to warfarin for stroke prophylaxis in patients with atrial fibrillation. Yet there is substantial lack of information on how patients on NOACs are currently treated when they have an acute ischemic stroke and the best strategies for treating intracerebral hemorrhage for those on chronic anticoagulation with warfarin or a NOAC. These are critical unmet needs for real world clinical decision making in these emergent patients.. The ARAMIS Registry is a multicenter cohort study of acute stroke patients who were taking chronic anticoagulation therapy prior to admission and are admitted with either an acute ischemic stroke or intracerebral hemorrhage. Built upon the existing infrastructure of American Heart Association/American Stroke Association Get With the Guidelines Stroke, the ARAMIS Registry will enroll a total of approximately 10,000 patients (5000 with acute ischemic stroke who are taking a NOAC and 5000 with anticoagulation-related intracerebral hemorrhage who are on warfarin or a NOAC). The primary goals of the ARAMIS Registry are to provide a comprehensive picture of current treatment patterns and outcomes of acute ischemic stroke patients on NOACs, as well as anticoagulation-related intracerebral hemorrhage in patients on either warfarin or NOACs. Beyond characterizing the index hospitalization, up to 2500 patients (1250 ischemic stroke and 1250 intracerebral hemorrhage) who survive to discharge will be enrolled in an optional follow-up sub-study and interviewed at 3 and 6 months after discharge to assess longitudinal medication use, downstream care, functional status, and patient-reported outcomes.. The ARAMIS Registry will document the current state of management of NOAC treated patients with acute ischemic stroke as well as contemporary care and outcome of anticoagulation-related intracerebral hemorrhage. These data will be used to better understand optimal strategies to care for these complex but increasingly common emergent real world clinical challenges.

Topics: Administration, Oral; Adult; Anticoagulants; Antithrombins; Atrial Fibrillation; Cohort Studies; Dabigatran; Emergency Treatment; Female; Humans; Male; Medication Therapy Management; Outcome and Process Assessment, Health Care; Pyrazoles; Pyridines; Pyridones; Quality Improvement; Registries; Rivaroxaban; Stroke; Thiazoles; United States; Warfarin

Edoxaban, an oral direct factor Xa inhibitor, has been found non-inferior to warfarin for preventing stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF), with a lower rate of intracranial bleeding. The aim of our investigation was to assess the cost-effectiveness of edoxaban versus warfarin from the perspective of the Italian health-care system. A Markov decision model was used to evaluate lifetime cost and quality-adjusted life expectancy of NVAF patients treated with warfarin or edoxaban. Transition probabilities were obtained from the ENGAGE AF-TIMI 48 trial, cost estimates were based on Italian prices and tariffs, utilities were obtained from the literature. One-way and second-order sensitivity analyses were performed. In the base case, lifetime costs were €18,658 for edoxaban and €14,060 for warfarin. Discounted quality-adjusted survival was 9.022 years for edoxaban and 8.425 years for warfarin, leading to an incremental cost-utility ratio of €7,713 per quality-adjusted life year (QALY) gained. Results were sensitive to time horizon, time in therapeutic range of warfarin and to the relative impact of warfarin versus edoxaban therapy onto quality of life. Probabilistic sensitivity analysis showed edoxaban to be cost-effective versus warfarin in 92.3 % of the simulations at a willingness-to-pay threshold of €25,000 per QALY. In conclusion, edoxaban proved to be a cost-effective alternative to warfarin in patients with moderate-to-high-risk NVAF.

Topics: Anticoagulants; Atrial Fibrillation; Cost-Benefit Analysis; Humans; Intracranial Hemorrhages; Italy; Markov Chains; Pyridines; Quality-Adjusted Life Years; Stroke; Thiazoles; Warfarin

Medical costs that may be avoided when any of the four new oral anticoagulants (NOACs), dabigatran, rivaroxaban, apixaban, and edoxaban, are used instead of warfarin for the treatment of non-valvular atrial fibrillation (NVAF) were estimated and compared. Additionally, the overall differences in medical costs were estimated for NVAF and venous thromboembolism (VTE) patient populations combined.. Medical cost differences associated with NOAC use vs warfarin or placebo among NVAF and VTE patients were estimated based on clinical event rates obtained from the published trial data. The clinical event rates were calculated as the percentage of patients with each of the clinical events during the trial periods. Univariate and multivariate sensitivity analyses were conducted for the medical-cost differences determined for NVAF patients. A hypothetical health plan population of 1 million members was used to estimate and compare the combined medical-cost differences of the NVAF and VTE populations and were projected in the years 2015-2018.. In a year, the medical-cost differences associated with NOAC use instead of warfarin were estimated at -$204, -$140, -$495, and -$340 per patient for dabigatran, rivaroxaban, apixaban, and edoxaban, respectively. In 2014, among the hypothetical population, the medical-cost differences were -$3.7, -$4.2, -$11.5, and -$6.6 million for NVAF and acute VTE patients treated with dabigatran, rivaroxaban, apixaban, and edoxaban, respectively. In 2014, for the combined NVAF, acute VTE, and extended VTE patient populations, medical-cost differences were -$10.0, -$10.9, -$21.0, and -$21.0 million for dabigatran, rivaroxaban, 2.5 mg apixaban, and 5 mg apixaban, respectively. Medical-cost differences associated with use of NOACs were projected to steadily increase from 2014 to 2018.. Medical costs are reduced when NOACs are used instead of warfarin/placebo for the treatment of NVAF or VTE, with apixaban being associated with the greatest reduction in medical costs.

Topics: Anticoagulants; Atrial Fibrillation; Cost-Benefit Analysis; Costs and Cost Analysis; Dabigatran; Health Expenditures; Hemorrhage; Humans; Models, Econometric; Myocardial Infarction; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; United States; Venous Thromboembolism; Warfarin

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Embolism; Humans; Pyridines; Stroke; Thiazoles; United States; United States Food and Drug Administration; Venous Thromboembolism

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Contraindications; Dabigatran; Drug Interactions; Drug Monitoring; Drug Substitution; Female; Hemorrhage; Humans; Kidney Diseases; Kidney Function Tests; Male; Morpholines; Pyrazoles; Pyridines; Pyridones; Risk Factors; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Thrombophilia

Topics: Atrial Fibrillation; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Approval; Embolism; Humans; Pyridines; Recurrence; Stroke; Thiazoles; Venous Thromboembolism; Warfarin

Stroke and venous thromboembolism (VTE) affect millions of patients. The vitamin K antagonist, warfarin, has been the main oral anticoagulant used to treat these conditions despite many limitations associated with its use. Recently, multiple novel oral anticoagulants have been approved and are reshaping how patients with atrial fibrillation (AF) at risk of stroke and patients with VTE are treated. The direct thrombin inhibitor, dabigatran etexilate , is among these novel agents that have been developed to overcome limitations with warfarin.. In this article, authors describe the pharmacokinetic and pharmacodynamic properties of dabigatran etexilate and summarize the clinical evidence and controversy surrounding its use in the US, Canada and Europe.. Dabigatran has demonstrated similar efficacy and safety to enoxaparin for VTE prevention in patients undergoing hip and knee arthroplasty, and to warfarin for the treatment of VTE. Dabigatran (110 mg) is noninferior and dabigatran (150 mg) is superior to warfarin for stroke prevention in patients with nonvalvular AF, with a lower rate of intracranial hemorrhage reported at both doses. Apixaban, rivaroxaban and edoxaban provide alternate anticoagulant options to dabigatran. While there are many similarities, there are also significant differences to consider in agent selection based on patient-specific characteristics.

Topics: Antithrombins; Arthroplasty, Replacement, Knee; Atrial Fibrillation; Cardiovascular Diseases; Clinical Trials as Topic; Dabigatran; Enoxaparin; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Venous Thromboembolism

In non-valvular atrial fibrillation (AF), oral anticoagulation reduces the risk of thromboembolism such as stroke and systemic embolism (SSE), but increases the risk of major bleeding such as intracranial haemorrhage (ICH). The risk-benefit balance between SSE versus ICH can be expressed as the net clinical benefit (NCB); however, the risk of SSE and ICH varies according to clinical factors that can be assessed using CHADS2, CHA2DS2-VASc (both quantifying risk of stroke) and HAS-BLED (quantifying risk of major bleeding) scores, respectively.. Using established modelling based on event rates for thromboembolism and haemorrhage in the Danish nationwide cohort study, we tested the hypothesis that edoxaban has a superior NCB compared with warfarin.. In our overall model, compared to no treatment, warfarin had a NCB of 0.26 (95% CI 0.24,0.28) events prevented per 100 patient years, edoxaban 60 mg daily a NCB of 0.71 [0.69,0.76], and edoxaban 30 mg daily a NCB of 0.71 [0.0.68,0.73]. When compared to no treatment, both doses of edoxaban have superior NCB values than those of warfarin at all CHADS2 and CHA2DS2-VASc scores. At CHADS2 ≥2 and CHA2DS2-VASc ≥2, edoxaban 60 mg dose had a better NCB than the 30 mg dose or warfarin, when compared to no treatment. With HAS-BLED score ≥3, both doses of edoxaban had a positive NCB compared to warfarin, at CHADS2 or CHA2DS2-VASc ≥2.. Our modelling study suggests that both 30 mg and 60 mg doses of edoxaban have a favourable NCB compared to warfarin, and the degree of benefit differs according to CHADS2, CHA2DS2-VASc and HAS-BLED scores. At CHA2DS2-VASc score ≥2, both edoxaban doses were superior to warfarin, but compared to no treatment, the 60 mg dose had a better NCB than the 30 mg dose or warfarin.

Topics: Atrial Fibrillation; Dose-Response Relationship, Drug; Europe; Factor Xa Inhibitors; Female; Humans; Incidence; Male; Models, Theoretical; Population Surveillance; Pyridines; Retrospective Studies; Risk Assessment; Risk Factors; Stroke; Survival Rate; Thiazoles; Treatment Outcome

The purpose of this analysis was to assess the cost-effectiveness of apixaban 5 mg BID versus high- and low-dose edoxaban (60 mg and 30 mg once daily) as intended starting dose strategies for stroke prevention in patients from a UK National Health Service perspective.. A previously developed and validated Markov model was adapted to evaluate the lifetime clinical and economic impact of apixaban 5 mg BID versus edoxaban (high and low dose) in patients with nonvalvular atrial fibrillation. A pairwise indirect treatment comparison was conducted for clinical end points, and price parity was assumed between apixaban and edoxaban. Costs in 2012 British pounds, life-years, and quality-adjusted life-years (QALYs) gained, discounted at 3.5% per annum, were estimated.. Apixaban was predicted to increase life expectancy and QALYs versus low- and high-dose edoxaban. These gains were achieved at cost-savings versus low-dose edoxaban, thus being dominant and nominal increases in costs versus high-dose edoxaban. The incremental cost-effectiveness ratio of apixaban versus high-dose edoxaban was £6763 per QALY gained.. Apixaban was deemed to be dominant (less costly and more effective) versus low-dose edoxaban and a cost-effective alternative to high-dose edoxaban.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Cost-Benefit Analysis; Female; Humans; Male; Markov Chains; Pyrazoles; Pyridines; Pyridones; Quality-Adjusted Life Years; Stroke; Thiazoles

Topics: Adult; Anticoagulants; Atrial Fibrillation; Drug Approval; Germany; Humans; National Health Programs; Pulmonary Embolism; Pyridines; Stroke; Thiazoles; Thromboembolism; Venous Thrombosis

Topics: Anticoagulants; Atrial Fibrillation; Embolism; Hemorrhage; Humans; Pyridines; Randomized Controlled Trials as Topic; Risk; Stroke; Thiazoles; Warfarin

Large Phase 3 clinical trials for stroke prevention in atrial fibrillation (AF) have compared non-vitamin K antagonist oral anticoagulants (NOACs) against warfarin, with the edoxaban trial only recently reported. In the absence of head to head trials directly comparing these NOACs against each other, we compared the efficacy and safety of edoxaban to other agents by an indirect comparison analysis. We performed an indirect comparison analysis of edoxaban (2 dose strategies) against apixaban (1 dose), dabigatran etexilate (2 doses) and rivaroxaban (1 dose), for their relative efficacy and safety against each other. For high-dose edoxaban vs apixaban, there were no significant differences in efficacy endpoints, mortality, myocardial infarction and major bleeding. Apixaban was associated with less major or clinically relevant non-major bleeding (hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.70-0.90) and gastrointestinal bleeding (HR 0.72; 95% CI 0.53-0.99). For dabigatran 110 mg twice daily, there were no significant differences in the main efficacy or safety endpoints. Dabigatran 150 mg bid was associated with lower stroke/systemic embolism (SE) (HR 0.75; 95% CI 0.56-0.99), stroke (HR 0.73; 95% CI 0.55-0.96) and haemorrhagic stroke (HR 0.48; 95% CI 0.23-0.99). There were no significant differences between high-dose edoxaban vs rivaroxaban for efficacy endpoints or mortality, but rivaroxaban had more major and/or clinically relevant non-major bleeding. When compared to low-dose edoxaban, apixaban was associated with lower stroke/SE (HR 0.70; 95% CI 0.55-0.89), stroke (HR 0.70; 95% CI 0.55-0.92) and ischaemic stroke (HR 0.65; 95% CI 0.50-0.89), but more major bleeding (HR 1.47; 95% CI 1.20-1.80). For dabigatran 110 mg bid, there were no significant differences in the efficacy endpoints, but dabigatran 110 mg bid had higher major (and gastrointestinal) bleeding. Dabigatran 150 mg bid and rivaroxaban were associated with lower stroke/SE and ischaemic stroke, but higher bleeding rates. In the present analysis, we have provided for the first time, comparisons of efficacy and safety of edoxaban against other NOACs. Notwithstanding the significant limitations of an indirect comparison analysis, some differential effects are evident with the NOACs for stroke prevention, allowing us to allow the prescriber a 'choice' to be able to fit the drug to the patient clinical profile (and vice versa).

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Clinical Trials, Phase III as Topic; Dabigatran; Female; Hemorrhage; Humans; Male; Middle Aged; Morpholines; Myocardial Infarction; Precision Medicine; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Survival Analysis; Thiazoles; Thiophenes; Treatment Outcome

Topics: Anticoagulants; Atrial Fibrillation; Clinical Trials as Topic; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Humans; Pyridines; Stroke; Thiazoles; Warfarin

New oral anticoagulants (NOACs) offer an alternative to warfarin for preventing stroke in patients with atrial fibrillation. NOACs are expected to replace warfarin and other vitamin K antagonists for most of their indications in the future. Knowledge of the use of NOACs in the perioperative period is important for optimal care.. Studies that reported on the use of NOACs were identified, focusing on evidence-based guidance relating to the perioperative period. PubMed was searched for relevant articles published between January 2000 and January 2014.. The anticipated expanded clinical use of NOACs such as rivaroxaban (Xarelto™), apixaban (Eliquis™) and dabigatran (Pradaxa™) has the potential to simplify perioperative anticoagulant management because of fewer drug-drug interactions, rapid onset of action, predictable pharmacokinetics and relatively short half-lives. However, coagulation status cannot be monitored by international normalized ratio and no antidotes are currently available. In elective surgery, it is important to discontinue the use of NOACs, with special consideration of renal function as route of elimination. Guidelines for the management of bleeding complications in patients on NOACs are provided, and may be considered for trauma and emergency surgery. Haemodialysis could be considered for bleeding with use of dabigatran. Better options for reversal of the effects of NOACs when bleeding occurs may follow with novel drugs.. Management of NOACs in elective and emergency conditions requires knowledge of time of last intake of drug, current renal function and the planned procedure in order to assess the overall risk of bleeding. Currently no antidote exists to reverse the effects of these drugs.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Biological Availability; Clinical Trials as Topic; Dabigatran; Drug Monitoring; Elective Surgical Procedures; Emergencies; Half-Life; Hemorrhage; Humans; Medication Adherence; Morpholines; Preoperative Care; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Time Factors; Warfarin

Atrial fibrillation (AF), the most frequent sustained arrhythmia, is associated with an increased risk of thromboembolic events. The risk of stroke depends on risk factors such as age, hypertension, heart failure, and vascular disease. Thus, antithrombotic therapy is a cornerstone in the management of AF. Warfarin is successfully used to reduce thromboembolic events. More recently, direct thrombin (dabigatran) and factor Xa (apixaban, edoxaban, rivaroxaban) inhibitors have been compared to warfarin in large randomized trials. All new substances have been shown to be non-inferior to warfarin concerning thromboembolic events. Severe bleeding, such as fatal and intracranial bleeding, was less frequent with direct oral anticoagulants. Results of the studies and subgroup analyses are discussed. Further trials using direct oral anticoagulants in special populations such as very old and patients with kidney disease are needed.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Embolism; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Risk Factors; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Warfarin

Topics: Adult; Atrial Fibrillation; Dose-Response Relationship, Drug; Double-Blind Method; Factor Xa Inhibitors; Humans; Pyridines; Randomized Controlled Trials as Topic; Stroke; Thiazoles; Treatment Outcome; Warfarin

Edoxaban recently proved non-inferior to warfarin for prevention of thromboembolism in patients with non-valvular atrial fibrillation (AF). We conducted an imputed-placebo analysis with estimates of the proportion of warfarin effect preserved by each non vitamin K antagonist oral anticoagulant (NOAC) and indirect comparisons between edoxaban and different NOACs.. We performed a literature search (up to January 2014), clinical trials registers, conference proceedings, and websites of regulatory agencies. We selected non-inferiority randomised controlled phase III trials of dabigatran, rivaroxaban, apixaban and edoxaban compared with adjusted-dose warfarin in non-valvular AF. Compared to imputed placebo, all NOACs reduced the risk of stroke (ORs between 0.24 and 0.42, all p<0.001) and all-cause mortality (ORs between 0.55 and 0.59, all p<0.05). Edoxaban 30 mg and 60 mg preserved 87% and 112%, respectively, of the protective effect of warfarin on stroke, and 133% and 121%, respectively, of the protective effect of warfarin on all-cause mortality. The risk of primary outcome (stroke/systemic embolism), all strokes and ischemic strokes was significantly higher with edoxaban 30 mg than dabigatran 150 mg and apixaban. There were no significant differences between edoxaban 60 mg and other NOACs for all efficacy outcomes except stroke, which was higher with edoxaban 60 mg than dabigatran 150 mg. The risk of major bleedings was lower with edoxaban 30 mg than any other NOAC, odds ratios (ORs) ranging between 0.45 and 0.67 (all p<0.001).. This study suggests that all NOACs preserve a substantial or even larger proportion of the protective warfarin effect on stroke and all-cause mortality. Edoxaban 30 mg is associated with a definitely lower risk of major bleedings than other NOACs. This is counterbalanced by a lower efficacy in the prevention of thromboembolism, although with a final benefit on all-cause mortality.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Humans; Meta-Analysis as Topic; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Vitamin K; Warfarin

Recent randomized clinical trials (RCTs) have evaluated the benefit of new oral anticoagulants in reducing the risk of vascular events and bleeding complications in patients with atrial fibrillation (AF). However, abundant and strict enrollment criteria may limit the validity and applicability of results of RCTs to clinical practice. We estimated the eligibility for participation in RCTs of an unselected group of patients with AF. In addition, we compared features favoring new oral anticoagulant use between patients with versus without stroke. Randomized Evaluation of Long-Term Anticoagulation Therapy. We applied enrollment criteria of 4 RCTs (RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE-AF-TIMI 48) to 695 patients with AF taking warfarin, prospectively and consecutively collected at a university medical center; 500 patients with and 195 patients without stroke. Time in therapeutic range and bleeding risk scheme (anticoagulation and risk factors in atrial fibrillation) were also measured.. The proportions of patients fulfilling the trial enrollment criteria varied, ranging from 39% to 72.8%, depending on the differences in indications/contraindications among studies and presence/absence of stroke. The main reasons for ineligibility for RCTs were hemorrhagic risk (anticoagulation and risk factors in atrial fibrillation [ATRIA] score) (10.8%-40.5%) and planned cardioversion (5.1%-7.7%) for nonstroke patients, and a low creatinine clearance (5.6%-9.2%) and higher risk of bleeding (15.2%-20.8%) for patients with stroke. When compared with nonstroke patients, patients with stroke showed a lower time in therapeutic range (54.4±42.8% versus 65.4±34.9%, especially with severe disability) and a high hemorrhagic risk (ATRIA score) (3.06±2.30 versus 2.18±2.16) (P<0.05 in both cases).. Patients enrolled in RCTs are partly representative of patients with AF in clinical practice. When time in therapeutic range and bleeding tendency with warfarin use were considered, the use of new oral anticoagulants was preferred in patients with stroke than in nonstroke patients, but they were more likely to be excluded in RCTs.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Female; Humans; Male; Morpholines; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Research Design; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Warfarin

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Drug Administration Schedule; Factor Xa Inhibitors; Humans; Pyridines; Randomized Controlled Trials as Topic; Stroke; Thiazoles; Warfarin

Topics: Anticoagulants; Atrial Appendage; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Septal Occluder Device; Stroke; Thiazoles; Thiophenes; Unnecessary Procedures; Warfarin

Topics: Acenocoumarol; Anticoagulants; Benzamides; Benzimidazoles; beta-Alanine; Dabigatran; Heparin; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Thromboembolism; Thrombosis; Warfarin

Although currently available anticoagulants are effective for the prevention and treatment of thromboembolic disorders, they have several drawbacks. Low molecular weight heparin and fondaparinux produce a predictable level of anticoagulation that obviates the need for coagulation monitoring, but they must be given parenterally, which renders them inconvenient for long-term use. Vitamin K antagonists, such as warfarin, are administered orally, but produce a variable anticoagulant response because genetic polymorphisms, dietary vitamin K intake and multiple drug-drug interactions affect their metabolism. Consequently, coagulation monitoring and frequent dose adjustments are needed to ensure that a therapeutic level of anticoagulation is achieved. This is burdensome for patients and physicians, and costly for the healthcare system. These limitations have prompted the development of new oral anticoagulants that target thrombin or factor Xa. The new agents produce such a predictable anticoagulant response that they can be given in fixed doses without monitoring. This paper focuses on the new oral anticoagulants in the most advanced stages of development.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; Clinical Trials as Topic; Dabigatran; Drug Discovery; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Thrombin; Venous Thromboembolism; Vitamin K

Vitamin K antagonists have been the cornerstone of oral antithrombotic therapy to help prevent ischemic stroke in atrial fibrillation (AF) and reduce venous thromboembolic events. Despite proven clinical benefit, vitamin K antagonists have several limitations, including a narrow therapeutic window, slow onset/offset of action, need for close monitoring and significant drug/food interactions, highlighting the need for alternative therapies. Recently, the direct thrombin inhibitor dabigatran was approved by the US FDA for use in AF, and several factor Xa inhibitors are in late-stage clinical testing. Edoxaban is a novel, oral, reversible, direct factor Xa inhibitor with rapid absorption and predictable dose-dependent anticoagulation effects. Early clinical studies have shown promising results and it is currently undergoing large-scale Phase III trials for stroke prevention in AF and venous thromboembolic event prophylaxis and treatment. This review provides an overview of the current understanding, clinical trial results and pharmacology of edoxaban.

Topics: Anticoagulants; Atrial Fibrillation; Clinical Trials as Topic; Factor Xa Inhibitors; Humans; Pyridines; Stroke; Thiazoles; Venous Thromboembolism

Edoxaban is an oral direct factor Xa inhibitor that is currently undergoing investigation in phase III clinical trials for the prevention of stroke in patients with atrial fibrillation (AF) and for the prevention and treatment of venous thromboembolic events (VTE). Factor Xa is an attractive target for anticoagulant treatment, as it is the primary and rate-limiting source of amplification in the coagulation cascade. Edoxaban is a competitive inhibitor of factor Xa and has >10 000-fold greater selectivity for factor Xa relative to thrombin. In phase I clinical trials, the anticoagulant effects of edoxaban included dose-dependent increases in activated partial thromboplastin time and prothrombin time following single edoxaban doses of 10-150 mg and after multiple ascending doses (60 mg twice daily, 90 mg daily and 120 mg daily). The anticoagulant effects of edoxaban were rapid in onset (time to peak plasma concentration 1-2 hours) and sustained for up to 24 hours. Prolongation of bleeding time in 8% of subjects was >9.5 minutes (none of which appeared to be clinically significant) 2 hours after initial dosing, and was independent of edoxaban dose, formulation or dietary state. In general, plasma edoxaban concentrations were linearly correlated with coagulation parameters. Phase II clinical trials in patients with AF and VTE suggest that the edoxaban 30 mg once-daily and 60 mg once-daily regimens had a similar or better safety profile compared with dose-adjusted warfarin (international normalized ratio 2.0-3.0) in terms of bleeding events, and that edoxaban was not associated with hepatotoxicity. In addition, edoxaban was associated with statistically significant dose-dependent reductions in VTE after orthopaedic surgery compared with placebo or dalteparin sodium. Further clinical investigation of the efficacy and safety of once-daily edoxaban is being conducted in phase III clinical trials in comparison with warfarin in patients with AF in the phase III ENGAGE AF-TIMI 48 trial (NCT00781391), and in comparison with low-molecular weight heparin/warfarin in the prevention of recurrent VTE in patients with symptomatic deep vein thrombosis and/or pulmonary embolism in the HOKUSAI VTE trial (NCT00986154).

Topics: Administration, Oral; Animals; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Clinical Trials as Topic; Factor Xa Inhibitors; Humans; Pyridines; Rabbits; Rats; Stroke; Thiazoles; Venous Thrombosis