edoxaban and Hemorrhage

As the antithrombotic regimen that may best prevent ischaemic complications along with the lowest bleeding risk offset following transcatheter aortic valve implantation (TAVI) remains unclear, we aimed to compare the safety and efficacy of antithrombotic regimens in patients without having an indication for chronic oral anticoagulation.. We conducted a PROSPERO-registered (CRD42021247924) systematic review and network meta-analysis of randomized controlled trials evaluating post-TAVI antithrombotic regimens up to April 2022. We estimated the relative risk (RR) and 95% confidence intervals (95% CIs) using a random-effects model in a frequentist pairwise and network metanalytic approach. We included seven studies comprising 4006 patients with a mean weighted follow-up of 12.9 months. Risk of all-cause death was significantly reduced with dual antiplatelet therapy (DAPT) compared with low-dose rivaroxaban + 3-month single antiplatelet therapy (SAPT) (RR 0.60, 95% CI 0.41-0.88), while no significant reduction was observed with SAPT vs. DAPT (RR 1.02, 95% CI 0.67-1.58) and SAPT and DAPT compared with apixaban or edoxaban (RR 0.60, 95% CI 0.32-1.14 and RR 0.59, 95% CI 0.34-1.02, respectively). SAPT was associated with a significant reduction of life-threatening, disabling, or major bleeding compared with DAPT (RR 0.45, 95% CI 0.29-0.70), apixaban or edoxaban alone (RR 0.45, 95% CI 0.25-0.79), and low-dose rivaroxaban + 3-month SAPT (RR 0.30, 95% CI 0.16-0.57). There were no differences between the various regimens with respect to myocardial infarction, stroke, or systemic embolism.. Following TAVI in patients without an indication for chronic oral anticoagulant, SAPT more than halved the risk of bleeding compared with DAPT and direct oral anticoagulant-based regimens without significant ischaemic offset.

Topics: Anticoagulants; Drug Therapy, Combination; Fibrinolytic Agents; Hemorrhage; Humans; Network Meta-Analysis; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Rivaroxaban; Transcatheter Aortic Valve Replacement

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

Previous preliminary clinical trials have confirmed that edoxaban can be efficacious for venous thromboembolism (VTE). This meta-analysis was considered to evaluate edoxaban's short-term efficacy and safety for venous thromboembolism after arthroplasty.. A comprehensive search was performed in these databases: PubMed, MEDLINE, Web of Science, and EMBASE on March 2022. All eligible trials should be randomized controlled trials (RCTs) when evaluating short-term efficacy and safety outcomes of edoxaban for VTE after total hip or knee arthroplasty.. Nine RCTs with 4274 patients were involved in this meta-analysis. Edoxaban in the VTE group prevented the incidence of VTE and indicated valuable clinical efficacy. The incidence of adverse events (AEs) and adverse drug reactions (ADRs) in the edoxaban group was decreased than that in other groups. Edoxaban increased the incidence of all bleeding events. However, in the edoxaban group and other groups, there was no statistical difference between major bleeding events and clinically relevant non-major or minor bleeding events. Edoxaban subgroups included edoxaban 15 mg, edoxaban 30 mg and edoxaban 60 mg prevented the incidence of VTE. Edoxaban 30 mg and 60 mg group increased the risk of all bleeding events. Edoxaban 30 mg can increase the incidence of major bleeding events. There was no difference in clinically relevant non-major or minor bleeding events. Edoxaban 30 mg can decrease the incidence of AEs.. Edoxaban was an efficacious and safe option to prevent and treat VTE in patients undergoing arthroplasty. However, we need further trials to explore edoxaban's long-term efficacy and safety.

Topics: Anticoagulants; Arthroplasty, Replacement, Knee; Hemorrhage; Humans; Pyridines; Thiazoles; Venous Thromboembolism

Cancer is a major risk factor for venous thromboembolism (VTE), and cancer-associated thrombosis (CAT) constitutes approximately 15-25% of all VTE cases. For decades, the standard treatment for CAT used to be daily subcutaneous low molecular weight heparin (LMWH). Data on the safety and efficacy of the direct oral anticoagulants (DOACs) in this population emerged only in recent years and specific DOACs were included into recent guidelines recommendations. In this narrative review of the literature, we reported the results of the phase III randomized controlled trials that evaluated the DOACs for the prevention and the acute treatment of CAT. For the acute phase treatment, the anti-Xa inhibitors (apixaban, edoxaban, rivaroxaban) showed better efficacy than LMWH in preventing VTE recurrence; however, rivaroxaban and edoxaban were also associated with an increased risk of bleeding events. For primary prevention of CAT in ambulatory cancer patients starting chemotherapy, apixaban and rivaroxaban showed better efficacy than placebo but a trend towards higher bleeding rates. Recent guidelines suggest the DOACs for the treatment of CAT in selected cancer patients (eg, low bleeding risk, no luminal gastrointestinal or genitourinary malignancies, no interfering medications). The DOACs are also suggested for primary thromboprophylaxis in selected ambulatory cancer patients at high risk of VTE (eg, Khorana score ≥2 prior to starting new chemotherapy, low bleeding risk, no interfering medications).

Topics: Administration, Oral; Anticoagulants; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Rivaroxaban; Thrombosis; Venous Thromboembolism

The efficacy and safety of direct oral anticoagulants (DOACs), including dabigatran, apixaban, rivaroxaban, and edoxaban, for preventing and treating venous thromboembolism (VTE) in patients with cancer is unclear.. We searched the PubMed, Embase, Web of Science, and Cochrane Library databases from the establishment to November 30, 2021. In the frequency-based network meta-analysis, the odds ratio with a 95% confidence interval was reported. The relative ranking probability of each group was generated based on the surface under the cumulative ranking curve (SUCRA).. We included 15 randomized controlled trials involving a total of 6162 patients. Apixaban reduced the risk of VTE compared with low-molecular heparin [OR = 0.53, 95% CI (0.32, 0.89)]. The efficacy of drugs was ranked from highest to lowest as follows: apixaban (SUCRA, 81.0), rivaroxaban (73.0), edoxaban (65.9), dabigatran (51.4), warfarin (30.8), and low-molecular-weight heparin (LMWH) (27.4). Edoxaban increased the risk of major bleeding compared with LMWH [OR = 1.83, 95% CI (1.04, 3.22)]. The safety of drugs was ranked from highest to lowest as follows: major bleeding-apixaban (SUCRA, 68.5), LMWH (55.1), rivaroxaban (53.0), warfarin (35.9), dabigatran (29.2), edoxaban (16.5) and clinically relevant non-major bleeding-LMWH (73.0), apixaban (57.8), edoxaban (45.8), rivaroxaban (35.3), and warfarin (10.8).. For preventing and treating VTE, in terms of VTE occurrence and major bleeding, apixaban had the lowest risk; in terms of clinically relevant non-major bleeding, LMWH had the lowest risk, followed by apixaban. Generally, apixaban is the most efficient and safest DOAC and presents better efficacy and relatively low bleeding risk among the VTE prevention and treatment drugs for patients with cancer.

Topics: Administration, Oral; Anticoagulants; Dabigatran; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Network Meta-Analysis; Rivaroxaban; Venous Thromboembolism; Warfarin

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

Topics: Anticoagulants; Antithrombins; Dabigatran; Embolism; Factor Xa Inhibitors; Heart Diseases; Heart Ventricles; Hemorrhage; Humans; Odds Ratio; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thrombosis; Warfarin

Anticoagulants are essential in the prevention of venous thromboembolism. However, the effectiveness and safety of different anticoagulants have always been controversial. Therefore, we aimed to expand the sample of anticoagulant results and rank the efficacy and safety of 19 anticoagulants in the prevention of venous thromboembolism when total knee or total hip arthroplasty procedure is performed.. A systematic review and network meta-analysis of randomized trials of adult patients undergoing total hip or knee arthroplasty were conducted. The trials were identified from PubMed, Web of Science, Cochrane Library, and Embase databases, in which anticoagulants were used as interventions randomized controlled trial. The incidence of venous embolism and bleeding are the key outcomes of assessing the efficacy of intervention drugs. We used the Physical Therapy Evidence Database (PEDro) to assess risk bias and used pairwise comparison and network meta-analysis with random effects to estimate the summary relative risk. The study has been registered with PROSPERO, number CRD42020200747.. From the 4083 identified manuscripts, 45,067 participants from 53 randomized trials were included in the analysis and randomly assigned to 19 anticoagulants. With Enoxaparin as a control, Rivaroxaban (risk difference 0.07, 95 % credible interval 0.06 to 0.08), Edoxaban (RD 0.09, 95 % CrI 0.08 to 0.11), and Apixaban (RD 0.05, 95 % CrI 0.04 to 0.06) had the best effect in preventing VTE. However, in terms of comprehensive bleeding rate, Apixaban, Edoxaban, and Darexaban were the most effective and stable. Although effective in preventing VTE, bleeding remains relatively high in Rivaroxaban. Enoxaparin is low-molecular-weight heparin that is widely used in clinics, and although its overall efficacy is not the best, its efficacy and safety are very stable.. According to the available data, Apixaban, Edoxaban, and Darexaban are better than any anticoagulants in the prevention of VTE and bleeding during total knee or total hip arthroplasty. In our study, Fondaparinux, Eribaxaban, Dalteparin, Betrixaban, Bemiparin, Reviparin, Acenocoumarol, and Tinzaparin were scarce in the included studies, therefore, more evidence is needed to prove their efficacy and safety.

Topics: Anticoagulants; Arthroplasty, Replacement, Knee; Enoxaparin; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiazoles; Venous Thromboembolism

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

Direct oral anticoagulants, anti-IIa or anti-Xa, are widely used in the treatment and prevention of venous thromboembolic disease as well as in nonvalvular atrial fibrillation. Direct oral anticoagulants are characterized by a rapid onset of activity, a predictable response and a relatively wide therapeutic window. Nevertheless, theoretical drug interactions exist since direct oral anticoagulants are substrates of the transport protein P-glycoprotein and/or of isoforms of cytochromes P450 pathway. Direct oral anticoagulants do not have a marketing authorization for the treatment of cancer-associated thrombosis unlike low-molecular-weight heparins which remain the gold standard treatment today. However, recent studies have compared low-molecular-weight heparins to direct oral anticoagulants in the treatment of cancer-associated thrombosis. Results of these studies showed a non-inferiority of direct oral anticoagulants in the prevention of recurrent thromboembolic events but at the cost of an increased hemorrhagic risk, in particular for patients with gastrointestinal and urogenital cancers. Thus, international guidelines, unlike French guidelines, integrate them in first line of the therapeutic strategy of cancer patients. We are certainly entering an era of personalized therapy for cancer-associated thrombosis, considering cancer type and also the theoretical risk of drug interactions with anti-cancer treatments or supportive care.

Topics: Anticoagulants; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; Cytochrome P-450 Enzyme System; Dabigatran; Drug Interactions; Factor Xa Inhibitors; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasm Proteins; Neoplasms; Pyrazoles; Pyridines; Pyridones; Recurrence; Rivaroxaban; Secondary Prevention; Thiazoles; Thrombosis; Venous Thromboembolism

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

Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. However, the risk of bleeding and all-cause mortality in patients with edoxaban versus vitamin K antagonists (VKAs) is unclear.. We systematically searched all published studies of edoxaban versus VKAs. PubMed, CENTRAL databases and www.clinicaltrial.gov were searched for relevant articles published from January 1966 to 20 February 2020. All phase III randomized controlled trials (RCTs) comparing the risk of bleeding and all-cause mortality in patients with edoxaban versus VKAs were included in our meta-analysis. Both random- and fixed-effects models were used to pool data across phase III RCTs.. We included four trials that met our inclusion criteria (n = 33,077). They included patients with atrial fibrillation (3 trials, n = 24,847), venous thromboembolism (VTE) or pulmonary embolism (PE) (1 trial, n = 8240). Edoxaban was associated with reduced risks of major or clinically relevant nonmajor bleeding (CRNM) events (OR: 0.78, 95% CI: 0.68-0.89), any bleeding events (OR: 0.76, 95% CI: 0.72-0.80), and intracranial bleeding events (OR: 0.38, 95% CI: 0.29-0.48). They had a similar risk of gastro-intestinal bleeding (OR: 0.95, 95% CI: 0.79-1.13), death from any cause (OR: 0.97, 95% CI: 0.80-1.19), stroke (OR: 1.00, 95% CI: 0.88-1.14) and systemic embolic events (OR: 0.93, 95% CI: 0.57-1.51) between edoxaban and VKAs.. Compared to VKAs, edoxaban is safe as a direct oral anticoagulant, with respect to reduced risk of major or CRNM, intracranial bleeding events, and similar risk of gastro-intestinal bleeding events and all-cause mortality.

Topics: Anticoagulants; Atrial Fibrillation; Fibrinolytic Agents; Hemorrhage; Humans; Pyridines; Randomized Controlled Trials as Topic; Thiazoles; Vitamin K

Non-vitamin K antagonist oral anticoagulants (NOACs) are a widely prescribed treatment to prevent stroke in patients with nonvalvular atrial fibrillation, and a therapy and preventative measure to prevent recurrences following venous thromboembolism. Optimal use of NOACs requires a thorough knowledge of the pharmacology of these drugs, as well as an understanding of patient factors affecting their use. The 4 NOACs-dabigatran, apixaban, edoxaban, and rivaroxaban are available in a range of doses suitable for differing indications and with a variety of dose reduction criteria. Identification of the correct dose is one of the key challenges in the individualization of treatment. Elderly patients with atrial fibrillation are at a greater risk of both ischemic and bleeding events than younger patients. Consequently, it is essential to achieve balance in anticoagulation strategies. Medication adherence to NOACs is important for safe and effective treatment, particularly in elderly populations. A growing body of evidence shows that once-daily dosing improves adherence and persistence to therapy, without having an impact on bleeding risk.

Topics: Administration, Oral; Age Factors; Aged; Aged, 80 and over; Antithrombins; Atrial Fibrillation; Dabigatran; Drug Administration Schedule; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Ischemic Stroke; Male; Medication Adherence; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Risk Factors; Rivaroxaban; Thiazoles; Time Factors; Treatment Outcome

Currently licenced direct oral anticoagulants selectively target thrombin (eg, dabigatran) or coagulation factor Xa (eg, apixaban, betrixaban, edoxaban, and rivaroxaban). Designed to be given in fixed doses without routine monitoring, direct oral anticoagulants have a lower propensity for food and drug interactions than do vitamin K antagonists, and in randomised controlled trials involving around 250 000 patients, they were at least as effective for prevention and treatment of thrombosis and were associated with a lower risk of life-threatening bleeding. The absolute benefits of direct oral anticoagulants over vitamin K antagonists are modest; however, guidelines recommend them in preference to vitamin K antagonists for most indications because of their ease of use and superior safety. The greatest benefits of direct oral anticoagulants are likely to be in patients who were previously deemed unsuitable for vitamin K antagonist therapy. The emergence of generic preparations is expected to further increase the uptake of direct oral anticoagulants, particularly in countries where they are currently not widely used because of cost. Direct oral anticoagulants are contraindicated in patients with mechanical heart valves and should be used with caution or avoided in patients with advanced kidney or liver disease. In this Therapeutics paper, we review the pharmacology of direct oral anticoagulants, summarise the evidence that led to their approval and incorporation into treatment guidelines, and explore key unresolved issues. We also briefly discuss future perspectives for the development of oral anticoagulants.

Topics: Administration, Oral; Anticoagulants; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Venous Thromboembolism

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

Direct oral anticoagulants (DOACs), including the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban have at least comparable efficacy as vitamin K antagonists along with a better safety profile, reflected by a lower incidence of intracranial hemorrhage. Specific reversal agents have been developed in recent years. Namely, idarucizumab, a specific antidote for dabigatran, is currently approved in most countries. Andexanet, which reverses factor Xa inhibitors, has been recently approved by the FDA, and ciraparantag, a universal antidote targeted to reverse all DOACs, is still under investigation. In this review we provide an update on the pharmacology of DOACs, the risk of hemorrhagic complications associated with their use, the measurement of their anticoagulant effect and the reversal strategies in case of DOAC-associated bleeding.

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Antidotes; Antithrombins; Blood Coagulation Factors; Dabigatran; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Risk Factors; Rivaroxaban; Thiazoles

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

Cancer patients with cancer-associated thrombosis (CAT) are at an elevated risk of recurrent venous thromboembolism (VTE) and of major bleeding while receiving treatment with anticoagulation. Recently, Xa inhibitors have been assessed in cancer patients for the treatment of CAT, providing clinicians and patients with more treatment options.. In this narrative review, the authors evaluate the evidence regarding the efficacy and safety of edoxaban, rivaroxaban, and apixaban in the treatment of CAT.. Xa inhibitors are an effective, safe, and convenient option for the treatment of CAT. Overall, they may be associated with a lower risk of recurrent VTE in cancer patients. Certain subgroups of cancer patients may be at increased risk of major bleeding while on treatment with Xa inhibitors, when compared to low-molecular-weight-heparin (LMWH). The current published data suggests an increase in gastrointestinal (GI) major bleeding in patients with GI malignancies. Other patient, treatment, and cancer characteristics may also be associated with a higher risk of major bleeding. Therefore, when assessing the appropriateness of Xa inhibitors for the treatment of CAT, the clinician must take into consideration the known interactions of these drugs, the individualized bleeding risk, and the patient's preferences, in order to make the best possible anticoagulation therapy recommendation.

Topics: Factor Xa Inhibitors; Hemorrhage; Humans; Neoplasms; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Venous Thromboembolism

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

Topics: Aged; Antibodies, Monoclonal, Humanized; Anticoagulants; Antidotes; Dabigatran; Female; Hemorrhage; Humans; Male; Pyrazoles; Pyridines; Pyridones; Risk; Rivaroxaban; Thiazoles

Topics: Administration, Oral; Aged; Antibodies, Monoclonal, Humanized; Anticoagulants; Atrial Fibrillation; Blood Coagulation Factors; Blood Coagulation Tests; Colonoscopy; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Male; Premedication; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Rivaroxaban; Thiazoles; Thromboembolism

Topics: Ambulatory Care; Anticoagulants; Dabigatran; Female; Hemorrhage; Humans; Length of Stay; Male; Neoplasms; Patient Discharge; Patient Selection; Pregnancy; Pregnancy Complications, Cardiovascular; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Rivaroxaban; Severity of Illness Index; Substance Abuse, Intravenous; Thiazoles

Rivaroxaban, dabigatran, apixaban and edoxaban are the four available new oral anticoagulants (NOAC) which are currently approved for venous thromboembolism prophylaxis after total hip and knee replacement. Large phase 3 and phase 4 studies comparing NOAC with low molecular weight heparins have shown similar results regarding the efficacy and safety of these two categories of anticoagulants. Management of bleeding complications is a matter of great significance. Three reversal agents have been developed: idarucizumab, andexanet alfa and ciraparantag. Idarucizumab is now commercially available. Regarding the perioperative management of NOAC, two main scientific groups have published their own recommendations. The European Heart Rhythm Association recommends 48-h period of stoppage preoperatively for factor Xa inhibitors and at least 3 or 4 days for dabigatran, while the French Study Group on Thrombosis and Haemostasis recommends 5-day discontinuation for all NOAC. Conventional clot tests can only be used as rough indicators for laboratory assessment of the activity of NOAC. Specific laboratory tests have been developed for more accurate measurements of NOAC blood levels, including a dilute thrombin time test (Hemoclot test) and the ecarin clot test for dabigatran and chromogenic anti-factor Xa assays for direct factor Xa inhibitors. Due to the beneficial properties of NOAC, these drugs are gaining ground in daily orthopaedic practice, and many studies are being conducted in order to extend the indications of these anticoagulants agents.

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Anticoagulants; Arginine; Blood Coagulation Tests; Dabigatran; Factor Xa; Hemorrhage; Humans; Orthopedic Procedures; Piperazines; Practice Guidelines as Topic; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; 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

Direct oral anticoagulants (DOACs) were developed to compensate for the demerits of warfarin. In Japan, three factor Xa inhibitors are used for the treatment of venous thromboembolism (VTE): edoxaban, rivaroxaban, and apixaban. Despite problems, such as the inability to monitor their effect and the lack of an antidote, these inhibitors have the same efficacy as conventional treatment with warfarin, and they are associated with a significantly high degree of safety in relation to hemorrhagic complications. East Asians, including Japanese, suffer from hemorrhage more frequently; therefore, DOACs are considered to be highly effective. Although there is no evidence to date, DOACs may be effective in a wide variety of ways, including the possibility that they prevent recurrence over the long term, reduce the length of hospitalization, allow treatment to be started on an outpatient basis, and be effective in cancer patients.

Topics: Administration, Oral; Anticoagulants; Clinical Trials as Topic; Factor Xa Inhibitors; Hemorrhage; Hospitalization; Humans; Japan; Neoplasms; Outpatients; Platelet Count; Pyrazoles; Pyridines; Pyridones; Recurrence; Rivaroxaban; Thiazoles; Venous Thromboembolism; 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

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

The goal of this study was to compare the relative efficacy and safety of different types of interventions for stroke prevention in patients with cardiovascular and cerebrovascular diseases.. This network meta-analysis (NMA) was conducted with a random effects model of Bayesian framework using Stata version 12.0. Odds ratios (ORs) and their credible intervals (CrIs) were applied for the efficacy and safety evaluation of various medical interventions, including aspirin, dipyridamole, ticlopidine, warfarin, and apixaban. In addition, the ranking of probability of every clinical outcome was estimated by comparing the surface under the cumulative ranking curve.. Compared with dabigatran, both edoxaban and aspirin + warfarin exhibited a higher rate of all-cause stroke (OR, 2.84 [95% CrI, 1.17-6.97]; OR, 3.42 [95% CrI, 1.20-9.84]). With respect to intracranial hemorrhage, aspirin + clopidogrel yielded worse outcomes than 7 treatments, including placebo, apixaban, aspirin, aspirin + dipyridamole, cilostazol, clopidogrel, and dabigatran (OR, 2.21 [95% CrI, 1.45-3.40]; OR, 2.11 [95% CrI, 1.05-4.17]; OR, 1.53 [95% CrI, 1.11-2.15]; OR, 1.78 [95% CrI, 1.01-3.03]; OR, 4.17 [95% CrI, 1.37-14.28]; OR, 1.85 [95% CrI, 1.22-2.86]; and OR, 2.56 [95% CrI, 1.37-4.76]). In terms of ischemic stroke, dabigatran provided better efficacy than placebo, aspirin, and aspirin + dipyridamole (OR, 0.36 [95% CrI, 0.18-0.72]; OR, 0.43 [95% CrI, 0.21-0.84]; and OR, 0.41 [95% CrI, 0.17-0.94]). As for mortality, dabigatran resulted in a lower mortality compared with aspirin, aspirin + clopidogrel, edoxaban, and warfarin (OR, 0.48 [95% CrI, 0.23-0.97]; OR, 0.40 [95% CrI, 0.17-0.92]; OR, 0.27 [95% CrI, 0.10-0.72]; and OR, 0.52 [95% CrI, 0.28-0.92]).. There are still some limitations to our NMA research. For instance, the lack of direct evidence for some therapies resulted in inconsistencies, particularly for warfarin compared with placebo and clopidogrel under different end points. Moreover, the included randomized controlled trials for patients with cardiovascular and cerebrovascular diseases are relatively broad, involving atrial fibrillation, myocardial infarction, and large-artery atherosclerosis stroke. Although further research is needed, dabigatran is highly recommended based on the present NAM for the treatment of cardiovascular and cerebrovascular diseases due to the drug's efficacy and safety.

Topics: Anticoagulants; Aspirin; Bayes Theorem; Cardiovascular Diseases; Clopidogrel; Dabigatran; Dipyridamole; Hemorrhage; Humans; Odds Ratio; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Thiazoles; Ticlopidine; Treatment Outcome; Warfarin

To conduct a systematic review of real-world (RWD) studies comparing the risk of major bleeding (MB) among patients with non-valvular atrial fibrillation (NVAF) on direct oral anticoagulants (DOACs) or warfarin.. MEDLINE, Embase, NHS-EED, and EconLit were searched for RWD studies published between January 2003 and November 2016 comparing MB risk among DOACs and warfarin. Proceedings of clinical conferences from 2012 to 2016 were reviewed.. A total of 4218 citations were identified, 26 of which met eligibility criteria. Most studies were retrospective analyses of administrative claims databases and patient registries (n = 23 of 26); about half were based in the United States (n = 15). Apixaban showed a significantly lower risk of MB versus warfarin in all eight included studies. MB risk was either significantly lower (n = 9 of 16) or not significantly different (n = 7 of 16) between dabigatran and warfarin; there was no significant difference between rivaroxaban and warfarin in all seven included studies. The risk was significantly lower with apixaban versus rivaroxaban (n = 7 of 7) but not significantly different from dabigatran (n = 6 of 7). MB risk was significantly lower (n = 3 of 4) or not significantly different (n = 1 of 4) with dabigatran versus rivaroxaban. No evidence was identified for edoxaban.. DOACs were associated with similar or lower risks of MB versus warfarin. A lower MB risk was consistently observed for apixaban, but less consistently for dabigatran; MB risk was similar between rivaroxaban and warfarin. Among DOACs, the risk of MB with apixaban was consistently lower than with rivaroxaban, but similar to dabigatran.

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

Antithrombotic therapy using new oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) has been generally shown to have a favorable risk-benefit profile. Since there has been dispute about the risks of gastrointestinal bleeding (GIB) and intracranial hemorrhage (ICH), we sought to conduct a systematic review and network meta-analysis using Bayesian inference to analyze the risks of GIB and ICH in AF patients taking NOACs.. We analyzed data from 20 randomized controlled trials of 91 671 AF patients receiving anticoagulants, antiplatelet drugs, or placebo. Bayesian network meta-analysis of two different evidence networks was performed using a binomial likelihood model, based on a network in which different agents (and doses) were treated as separate nodes. Odds ratios (ORs) and 95% confidence intervals (CIs) were modeled using Markov chain Monte Carlo methods.. Indirect comparisons with the Bayesian model confirmed that aspirin+clopidogrel significantly increased the risk of GIB in AF patients compared to the placebo (OR 0.33, 95% CI 0.01-0.92). Warfarin was identified as greatly increasing the risk of ICH compared to edoxaban 30 mg (OR 3.42, 95% CI 1.22-7.24) and dabigatran 110 mg (OR 3.56, 95% CI 1.10-8.45). We further ranked the NOACs for the lowest risk of GIB (apixaban 5 mg) and ICH (apixaban 5 mg, dabigatran 110 mg, and edoxaban 30 mg).. Bayesian network meta-analysis of treatment of non-valvular AF patients with anticoagulants suggested that NOACs do not increase risks of GIB and/or ICH, compared to each other.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Bayes Theorem; Clinical Trials as Topic; Dabigatran; Female; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Intracranial Hemorrhages; Male; Markov Chains; Middle Aged; Monte Carlo Method; Network Meta-Analysis; Odds Ratio; Pyridines; Randomized Controlled Trials as Topic; Risk; Thiazoles; Warfarin

The purpose of this review was to offer practical management strategies for when patients receiving direct oral anticoagulants require elective surgery or present with bleeding complications.. Clinical practice guidelines are now available on the timing of periprocedural interruption of treatment with the newer direct oral anticoagulants based on their pharmacodynamics and pharmacokinetics and based on findings from cohort studies and clinical trials. An antibody that reverses the effects of dabigatran is now available, and a factor Xa decoy is being developed as an antidote to apixaban, betrixaban, edoxaban, and rivaroxaban. The timing of interruption of direct oral anticoagulants for elective surgery is based on multiple factors, including pharmacologic properties and interactions, the patient's renal function, and the type of planned surgery. There is little role for low-molecular-weight heparin bridging. Idarucizumab is the treatment of choice for dabigatran-related life-threatening bleeding, while andexanet alfa is being developed to reverse factor Xa inhibitors.

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Anticoagulants; Antidotes; Antithrombins; Benzamides; Blood Loss, Surgical; Dabigatran; Deprescriptions; Elective Surgical Procedures; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Practice Guidelines as Topic; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiazoles

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

The direct oral anticoagulants (DOACs), also referred to as novel (or non-vitamin K antagonist) oral anticoagulants (NOACs), represent a major development in anticoagulation therapy due to their rapid onset of action, predictable dose-response with fixed doses and limited interactions with food and drugs.

Topics: Administration, Oral; Anticoagulants; Dabigatran; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Risk Factors; Rivaroxaban; 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

Venous thromboembolism (VTE) is a common complication that manifests during and/or after hospitalization, as well as postsurgeries including orthopedic surgeries. Edoxaban is a new oral direct factor Xa inhibitor that has been recently approved for treating VTE in patients who have already been treated with a parenteral anticoagulant and for the prevention of stroke and non-central nervous system systemic embolism in patients with nonvalvular atrial fibrillation.. The purpose of this systematic review was to evaluate the safety and efficacy of edoxaban for VTE prophylaxis after lower limb orthopedic surgery.. A comprehensive search was conducted in Google Scholar, PubMed, MEDLINE, and ScienceDirect to identify potential records, then titles, abstracts, and full texts were screened using the inclusion criteria to filter out irrelevant studies. Moreover, the data extraction and quality assessment were undertaken using standardized tools, and the results were narratively synthesized and presented in tables.. Six studies were included in this systematic review after screening 2989 records. The majority of studies demonstrated a statistically significant reduction in VTE events in the edoxaban group(s) compared to the dalteparin, placebo, or enoxaparin groups (P < .05). The differences in VTE cases in some studies reached to approximately 50% favoring edoxaban 30 mg over the comparator (P < .05). However, other studies uncovered a statistically insignificant difference between edoxaban and the comparator "enoxaparin" when used for VTE prophylaxis (P > .05). On the other hand, although edoxaban found to cause more bleeding, the differences between edoxaban and the comparator are statistically insignificant (P > .05).. This study helped to amalgamate evidence with regard to the use of edoxaban for VTE prophylaxis post-lower limb orthopedic surgery. In line with the results of the reviewed studies, edoxaban seems to be highly effective in reducing VTE post-lower limb orthopedic surgery.

Topics: Administration, Oral; Drug Administration Schedule; Factor Xa Inhibitors; Hemorrhage; Humans; Orthopedic Procedures; Patient Safety; Pyridines; Risk Factors; Thiazoles; Treatment Outcome; Venous Thromboembolism

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

The available clinical data on target-specific oral anticoagulant (TSOAC) reversal agents that are currently in development or have been approved by the Food and Drug Administration (FDA) are reviewed.. The development of TSOACs such as dabigatran, rivaroxaban, edoxaban, and apixaban has presented benefits and new challenges. One of the main challenges associated with the use of TSOACs is the lack of suitable agent-specific reversal agents. Several treatment options for the management of life-threatening bleeding events associated with TSOAC use, such as fresh frozen plasma, prothrombin complex concentrates, and recombinant coagulation factor VIIa, have been used, with inconsistent results. Currently, two potential reversal agents for oral direct factor Xa inhibitors (andexanet alfa and ciraparantag) are at various stages of clinical development. Idarucizumab, a reversal agent for the oral direct thrombin inhibitor dabigatran, was approved by FDA in October 2015. Idarucizumab and andexanet alfa have been reported to produce anticoagulation reversal effects within minutes of administration. Ciraparantag was demonstrated to decrease whole blood clotting time to within 10% of baseline values in 10 minutes or less, with a return to baseline hemostasis in 10-30 minutes. TSOAC reversal agents have been generally well tolerated in clinical trials.. Idarucizumab and other TSOAC reversal agents, such as andexanet alfa and ciraparantag, present the potential for consistent and effective treatment and management options when life-threatening or uncontrolled TSOAC-associated bleeding occurs or when emergency surgery is warranted in patients using TSOACs.

Topics: Administration, Oral; Antithrombins; Dabigatran; Drug Evaluation; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; United States; United States Food and Drug Administration

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 effective in preventing and treating venous thromboembolism, and preventing stroke in atrial fibrillation. Until recently, there has been no specific reversal agent for DOACs. Now, a specific antidote for the direct thrombin inhibitor, dabigatran has been approved for use, and antidotes for factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) are being developed. We review the evidence for currently used and emerging reversal strategies, and discuss possible clinical implications, including increased prescription of DOACs, use of DOACs in clinical situations previously felt to pose too great a risk of bleeding, and use of reversal agents beyond currently approved indications.

Topics: Antibodies, Monoclonal, Humanized; Anticoagulants; Antithrombins; Arginine; Dabigatran; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Piperazines; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiazoles; Venous Thromboembolism

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

Emergency physicians make treatment decisions in patients who present to the emergency department (ED) with acute venous thromboembolism (VTE). They also encounter patients on target-specific oral anticoagulants (TSOACs) who require urgent intervention. New approvals and increasing prescriptions for TSOACs (e.g., apixaban, dabigatran, edoxaban, and rivaroxaban) for the management of several thromboembolic disorders warrant an evaluation of the impact of these agents in the ED setting.. This review discusses the use of TSOACs in the ED for the treatment of acute VTE, and highlights strategies for the management of patients on TSOACs who present to the ED with other complications, such as bleeding complications or requiring emergency surgery.. Apixaban, dabigatran, edoxaban, and rivaroxaban have been approved for the treatment of acute VTE. We discuss the impact of this on ED management of TSOAC-naïve patients and highlight results with TSOACs in high-risk subgroups including the elderly and those with prior VTE or active cancer. This review also discusses management strategies for patients on TSOACs. For emergency physicians, strategies for the management of bleeding, approaches to patient care when emergency surgery is needed, laboratory assays for measuring plasma concentrations of TSOACs, and drug-drug interactions are of special importance.. Familiarity with TSOACs will better position emergency physicians to provide state-of-the art care to their patients with VTE and help them manage potentially complicated circumstances related to the chronic use of these drugs.

Topics: Acute Disease; Administration, Oral; Anticoagulants; Blood Coagulation Tests; Dabigatran; Drug Interactions; Drug Monitoring; Emergency Service, Hospital; Factor Xa Inhibitors; Hemorrhage; Humans; Practice Guidelines as Topic; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Venous Thromboembolism

Stroke is the most serious clinical consequence of atrial fibrillation, which is the most common cardiac arrhythmia. Non-vitamin K antagonist oral anticoagulants (NOACs) have emerged as efficacious, safe and convenient stroke prevention agents. This updated network meta-analysis focused on the relative efficacy and safety of apixaban compared with dabigatran, rivaroxaban and edoxaban for stroke prevention in (i) patients with CHADS2 score ≥ 2, (ii) secondary stroke prevention, and (iii) patients with high quality anticoagulation control with warfarin.. A fixed-effects network meta-analysis was conducted, including data from four Phase III randomised controlled trials (> 70,000 patients with non-valvular atrial fibrillation). The results of the base-case analysis comparing NOACs with warfarin were broadly in line with the results from the individual trials. Results from the three subgroup analyses were broadly similar to the base case results. For example in patients with CHADS2 score ≥ 2, apixaban, high-dose dabigatran, rivaroxaban, and high-dose edoxaban had significantly lower hazards of stroke/systemic embolism compared with low-dose edoxaban. Apixaban and low-dose edoxaban were associated with significantly lower hazards of major bleeding compared with rivaroxaban and dabigatran 150 mg. However, several treatment comparisons that were significant in the base-case analysis were not significant in the patient subgroups, due to the reduced sample size of the subgroups compared with the overall population.. Among the NOACs, apixaban offered the most favourable efficacy and safety profile in the overall patient population as well as in the three subgroups investigated.

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

New oral anticoagulants (NOAC) and the Watchman device represent an alternative to warfarin for stroke prophylaxis in atrial fibrillation (AF) patients. However, no studies compare these new treatments. We performed a network meta-analysis to indirectly compare Watchman and NOACs among AF patients.. We performed a MEDLINE search for studies comparing warfarin with NOACs (dabigatran, rivaroxaban, apixaban and edoxaban) or Watchman in AF patients with reported clinical outcomes. Mixed treatment comparison model generation was performed to directly and indirectly compare NOACs, warfarin and Watchman.. 14 studies with 246,005 patients were included in the analysis, among which 124,823 were treated with warfarin, 120,450 were treated with NOACs and 732 had Watchman implanted. Mean age was 72 ± 9 years, 53% were male, and mean CHADS2 score was 2.1 ± 1.6. Both NOACs and Watchman were superior to warfarin in hemorrhagic stroke prevention (OR = 0.46 [0.30-0.82] and OR = 0.21 [0.05-0.99], respectively). NOACs significantly reduced total stroke (OR = 0.78 [0.58-0.96]) and major bleeding (OR = 0.78 [0.65-0.91]) compared with warfarin. Indirect comparison between NOAC and Watchman revealed no significant differences in outcomes, though there was a trend toward higher rates of ischemic stroke with Watchman compared with NOAC (OR 2.60 [0.60-13.96]) with the opposite findings with hemorrhagic stroke (OR = 0.44 [0.09-2.14]).. NOAC therapy was superior to warfarin for multiple outcomes while Watchman reduced hemorrhagic stroke. Further studies are needed to assess Watchman versus NOAC to optimize therapy for stroke prevention in AF patients.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Clinical Trials as Topic; Dabigatran; Defibrillators, Implantable; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Thiazoles; Warfarin

This article emphasizes the differentiated management of direct oral anticoagulants (DOACs)-associated bleeding in trauma patients to generate a severity adjusted treatment protocol.. The management of DOAC-associated bleeding should take severity, mortality risk, and haemodynamic effects of the trauma-induced bleeding into account.. The different pharmacological properties of DOACs are important for the management of trauma-induced bleeding. Comorbidities like renal impairment and liver dysfunction prolong their half-life. Patients with minor bleeding in stable clinical condition can be managed by a 'wait and see' approach. Moderate bleeding is suggested to be managed by a primarily conservative approach. In life-threatening bleeding, the administration of activated or nonactivated factor concentrates seems justified, together with supportive measures as part of an advanced management protocol. The administration of specific antidotes may be an alternative in the future. A monoclonal antibody to dabigatran (idarucizumab) has recently been approved by the Food and Drug Administration, whereas antidotes to Factor X activated inhibitors (andexanet and aripazine) are still under development. Sufficiently powered studies with clinical and safety outcome measures are still missing for all specific antidotes at this time.

Topics: Administration, Oral; Antifibrinolytic Agents; Antithrombins; Atrial Fibrillation; Clinical Protocols; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Plasma; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; United States; Wounds and Injuries

Only vitamin K antagonists could be applied as oral anticoagulants over the past six decades. Coumarols have narrow therapeutic range, and unpredictable anticoagulant effects are resulted by multiple drug interactions. Therefore, regular routine monitoring of the international normalized ratio is necessary. There are two groups of factor-specific anticoagulants: molecules with anti-FIIa (dabigatran) and anti-FXa (rivaroxaban, apixaban and edoxaban) effect. Author summarizes the most important clinical features of the new oral anticoagulants, their indications and the possibilities of laboratory controls. Bleedings are the most important side effects of anticoagulants. This review summarizes the current published evidences for new oral anticoagulants reversal (non-specific and specific) agents, especially in cases with severe acute bleedings or urgent surgery procedures. It reports on how to use inhibitors, the recommended doses and the most important clinical results. The review focuses on idarucizumab - already approved by the U.S. Food and Drug Administration and the European Medicines Agency - which has a key role as the first specific inhibitor of dabigatran.

Topics: Acute Disease; Administration, Oral; Ambulatory Care; Antibodies, Monoclonal, Humanized; Anticoagulants; Antidotes; Antithrombins; Dabigatran; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Severity of Illness Index; Surgical Procedures, Operative; Thiazoles

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

Gender differences have been reported in patients with acute VTE treated with antithrombotic drugs.. To address the relationship between gender and new oral anticoagulants (NOACs), we performed a meta-analysis to evaluate the incidence of recurrent VTE and major plus clinically relevant non-major bleedings in males and females, with acute VTE, treated with NOACs over the treatment period.. Systematic review and meta-analysis of double blind randomized controlled trials (RCTs).. MEDLINE, Cochrane Library of Clinical Trials (up to September 2015).. RCTs that compared the beneficial and harmful effects of NOAC drugs (apixaban, dabigatran, edoxaban and rivaroxaban).. Three authors abstracted data. Study-specific risk ratios (RR) were combined using random-effects model.. Nine studies including 16,372 patients were selected. No significant difference for the incidence of recurrent VTE was found between men and women. Compared to men, women had a higher incidence of major bleedings plus clinically relevant minor bleedings (5.3% and 7.9% respectively; RR: 0.635; 95% CI: 0.54-0.74; p<0.001). The subgroup analysis showed a significant gender difference in incidence of major bleedings and clinically relevant minor bleedings only for Edoxaban (RR: 0.52; 95% CI: 0.42-0.64; p<0.001).. This meta-analysis showed, compared to men, a higher risk of bleeding in women with acute VTE treated with NOACs. Future trials should evaluate the effect of gender on bleeding in patients with acute VTE treated with NOACs.

Topics: Administration, Oral; Anticoagulants; Dabigatran; Double-Blind Method; Female; Hemorrhage; Humans; Male; Middle Aged; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Sex Characteristics; Thiazoles; Treatment Outcome; Venous Thromboembolism

New oral anticoagulants (NOACs) have been developed in recent years and are increasingly used in clinical practice. Dabigatran is a direct thrombin (factor II) inhibitor while rivaroxaban, apixaban and edoxaban are direct inhibitors of factor Xa. The European Medicines Agency (EMA) currently approves these NOACs for different clinical uses. NOACs do not require routine monitoring of coagulation although an assessment of anticoagulation activity in these patients may be required in different conditions. NOACs show a similar or lower incidence of bleeding compared with conventional therapies in phase III trials. In case of bleeding, non-specific reversal strategies are available while specific reversal agents are the subject of ongoing trials. The role of this review is to summarize the current knowledge on NOCAs focusing on bleeding management in the perioperative period.

Topics: Administration, Oral; Anticoagulants; Clinical Trials, Phase III as Topic; Dabigatran; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; 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

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

Vitamin K antagonists are commonly used by clinicians to provide anticoagulation to patients who have or are at risk of having thrombotic events. In addition to familiarity with the dosing and monitoring of vitamin K antagonists, clinicians are accustomed to using vitamin K if there is a need to reverse the anticoagulant effect of vitamin K antagonists. There are now 4 new non-vitamin K antagonist oral anticoagulants (NOACs) that are attractive alternatives to vitamin K antagonists. Despite similar or lower rates of serious bleeding with NOACs in comparison with warfarin, there is a pressing need for strategies to manage bleeding when it does occur with NOACs and to reverse the pharmacological effect of these agents if needed. Important steps in minimizing bleeding risks with NOACs include dose adjustment of the agents in the setting of renal dysfunction and avoidance of the concomitant use of other antithrombotic agents if feasible. Laboratory measurement of the anticoagulant effect of NOACs is best accomplished with specialized assays, although some of the more widely available coagulation tests can provide information that is potentially useful to clinicians. Nonspecific hemostatic agents such as prothrombin complex concentrates and recombinant factor VIIa can be used to reverse the effect of NOACs. More specific reversing agents include the approved humanized monoclonal antibody fragment idarucizumab for reversing the effects of dabigatran, the investigational factor Xa decoy andexanet alfa, and the synthetic small molecule ciraparantag. Both andexanet and ciraparantag have been reported to reverse the effects of the anti-Xa NOACs (rivaroxaban, apixaban, and edoxaban), and a number of other anticoagulant agents in common clinical use, as well.

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Antithrombins; Arginine; Blood Coagulation Factors; Dabigatran; Factor VIIa; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Hemostatics; Humans; Piperazines; Plasma; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiazoles

Recently, a new generation of direct-acting oral anticoagulants (DOACs) with a greater specificity towards activated coagulation factors was introduced based on encouraging results for efficacy and safety in clinical studies. An initial limitation of these new drugs was the absence of an adequate strategy to reverse the effect if a bleeding event occurs or an urgent invasive procedure has to be carried out.. Specific reversing agents for DOACs have become available, however, and are now evaluated in clinical studies. For the anti-factor Xa agents (rivaroxaban, apixaban, and edoxaban) a number of studies have shown that the administration of prothrombin complex concentrate resulted in a correction of the prolonged prothrombin time and restored depressed thrombin generation after rivaroxaban treatment in a controlled trial in healthy human subjects. In view of the relatively wide availability of prothrombin complex concentrates, this would be an interesting option if the results can be confirmed in patients on oral factor Xa inhibitors who present with bleeding complications. More specific reversal can be achieved with andexanet, a new agent currently in development that competitively binds to the anti-factor Xa agents. For the direct thrombin inhibitor dabigatran, the administration of prothrombin complex concentrates showed variable results in various volunteer trials and efficacy at relatively high doses in animal studies. Recently, a Fab fragment of a monoclonal antibody (idarucizumab) was shown to be an effective reversal agent for dabigatran in human studies.. For the new generation of DOACs, several reversal strategies and specific antidotes are under evaluation, although most interventions need further evaluation in clinical trials.

Topics: Administration, Oral; Anticoagulants; Disease Management; Factor Xa Inhibitors; Hemorrhage; Humans; Incidence; Prothrombin Time; Pyrazoles; Pyridines; Pyridones; Risk Factors; Rivaroxaban; Thiazoles

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

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: Anticoagulants; Clinical Trials, Phase III as Topic; Dabigatran; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Warfarin

As expected with all antithrombotic agents, there is a risk of bleeding complications in patients receiving direct oral anticoagulants (DOACs) because of the DOAC itself, acute trauma, invasive procedures, or underlying comorbidities. For many bleeding events, a prudent course of action will be to withdraw the DOAC, then "wait and support" the patient, with the expectation that the bleeding event should resolve with time. Likewise, DOAC therapy may be interrupted ahead of a planned procedure, the stopping time being dependent on the agent involved and the patient's renal function. However, urgent reversal of anticoagulation is required in patients with serious or life-threatening bleeding or in those requiring urgent surgery or procedures. Novel specific reversal agents, either under development or recently approved, will need to be incorporated into local anticoagulation reversal protocols. For dabigatran-treated patients, idarucizumab recently has been approved for clinical use in cases of life-threatening or uncontrolled bleeding or when patients require emergency surgery or urgent procedures, both associated with a high risk of bleeding. As clinical experience with individual specific reversal agents grows, their roles in managing major bleeding events in DOAC-treated patients will become better defined. Future research, as well as ongoing use of idarucizumab, should help establish when it is appropriate to re-dose with idarucizumab, coadminister with prothrombin complex concentrates, or re-initiate DOAC after idarucizumab use. Ongoing trials should help identify the appropriate doses and expected durations of effect for andexanet alfa and ciraparantag, which are likely to vary depending on the individual oral anticoagulants.

Topics: Antibodies, Monoclonal, Humanized; Anticoagulants; Arginine; Clinical Protocols; Dabigatran; Emergency Treatment; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Hospitals; Humans; Patient Selection; Piperazines; Practice Guidelines as Topic; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Surgical Procedures, Operative; Thiazoles

Four target-specific oral anticoagulants (TSOA's) have been compared to a vitamin K antagonist for the treatment of acute venous thromboembolism (VTE): dabigatran (D), rivaroxaban (R), apixaban (A) and edoxaban (E). We performed an indirect comparison of the TSOA's, based on the six phase III trials identified (RE-COVER I, RE-COVER II, EINSTEIN-DVT, EINSTEIN-PE, AMPLIFY and Hokusai-VTE). There was no statistically significant difference in risk of recurrent VTE or all-cause mortality between the TSOA's. For major bleeding, the RR of an event was 0.42 (95% CI 0.21-0.87, p = 0.02) for A versus D, compared with 0.57 (95% CI 0.29-1.15, p = 0.12) for A versus R, 0.37 (95% CI 0.19-0.73, p < 0.001) for A versus E, 0.74 (95% CI 0.42-1.30, p = 0.30) for R versus D, 0.64 (95% CI 0.38-1.08, p = 0.10) for R versus E and 1.15 (95% CI 0.66-2.00, p = 0.62) for E versus D. For the composite endpoint of major or clinically relevant nonmajor bleeding, the RR was 0.71 (95% CI 0.53-0.96, p = 0.02) for A versus D, 0.47 (95% CI 0.37-0.61, p < 0.001) for A versus R, 0.54 (95% CI 0.42-0.70, p < 0.001) for A versus E, 1.50 (95% CI 1.17-1.92, p = 0.001) for R versus D, 1.15 (95% CI 0.95-1.39, p = 0.16) for R versus E and 1.31 (95% CI 1.02-1.68, p = 0.04) for E versus D. Overall, apixaban appears to be associated with a lower risk of bleeding than the other TSOA's. This analysis may be helpful to the clinician in trying to balance risk versus benefit in selecting a new anticoagulant. A dedicated randomized trial directly comparing the new agents would be required to confirm these results.

Topics: Acute Disease; Adult; Aged; Anticoagulants; Clinical Trials, Phase III as Topic; Dabigatran; Female; Hemorrhage; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Recurrence; Risk Assessment; Rivaroxaban; Survival Analysis; Thiazoles; Venous Thrombosis

The prevention and treatment of venous thromboembolism (VTE) remains a clinical challenge, primarily owing to drawbacks associated with the use of heparins and vitamin K antagonists (VKAs). These and other factors, including a growing elderly population, mean that VTE presents a continuing burden to patients and physicians. Anticoagulant therapy is a fundamental approach for VTE management. Non-VKA oral anticoagulants, including the factor Xa inhibitors apixaban, edoxaban and rivaroxaban, and the thrombin inhibitor dabigatran, have been studied in phase III trials across a spectrum of thromboembolic disorders. These agents offer simplified care, with similar or improved efficacy and safety outcomes compared with heparins and vitamin K antagonists. There are several factors a physician must consider when prescribing an anticoagulant. An important consideration with all anticoagulant use is bleeding risk, especially in high-risk groups such as the elderly or those with renal impairment or cancer. In orthopaedic patients, other risks include a need for surgical revision or blood transfusion, or wound complications. Therefore, the clinical benefits of an anticoagulant should ideally be balanced with any risks associated with the therapy. Quantitative benefit-risk assessments are lacking, and owing to differences in trial design the non-VKA oral anticoagulants cannot be compared directly. Based on trial and "real-life" data, this review will summarise the clinical data for the non-VKA oral anticoagulants in the prevention and treatment of VTE, focusing on the balance between the benefits and risks of anticoagulation with these drugs, and their potential impact on VTE management.

Topics: Administration, Oral; Anticoagulants; Blood Coagulation; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Female; Hemorrhage; Heparin; Humans; Male; Orthopedic Procedures; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Rivaroxaban; Thiazoles; Thromboembolism; Treatment Outcome; Venous Thromboembolism; Vitamin K

A meta-analysis was performed to evaluate the risk of major bleeding with the use of New Oral Anticoagulants (NOACs).. Randomized controlled trials (RCTs) comparing NOACs (rivaroxaban, dabigatran, apixaban, edoxaban and darexaban) with comparators were selected.. Fifty trials included 155,537 patients. Pooled analysis of all NOACs for all indications together demonstrated no significant difference between NOACs and comparators for risk of major bleeding (odds ratio [OR] 0.93, 95% CI 0.79-1.09). Pooled analysis also showed that NOACs caused significantly less major bleeding compared to vitamin K antagonists (VKA) (0.77, 0.64-0.91). The analysis for individual NOACs showed risk of major bleeding were not different with rivaroxaban, apixaban or dabigatran compared to pharmacologically active comparators or VKA. Indication specific analysis showed that NOACs were associated with significantly higher major bleeding after hip surgery (1.43, 1.02-1.99), in patients with acute coronary syndrome (ACS), (compared against placebo) (2.89, 2.01-4.14), and for medically ill patients (2.79, 1.69-4.60). For the treatment of acute venous thromboembolism (VTE) or pulmonary embolism (PE), NOACs were associated with significantly less bleeding (0.63, 0.44-0.90). No significant difference was found between NOACs and comparators in treatment of atrial fibrillation and for extended treatment of VTE.. Risk of major bleeding with new oral anticoagulants varies with their indication for use. New agents may be associated with comparatively less major bleeding compared to VKA. NOAC may increase the risk of major bleeding after hip surgery, ACS and acute medically ill patients; but may be associated with less bleeding in treatment of acute VTE/PE.

Topics: Administration, Oral; Antithrombins; Azepines; Benzamides; Benzimidazoles; beta-Alanine; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Risk; Rivaroxaban; Thiazoles; Thiophenes

Three factor Xa inhibitors have been studied in the treatment of venous thromboembolism, both for acute therapy and as extended therapy to prevent recurrent events. Rivaroxaban, apixaban, and edoxaban have all proven to be effective in Phase III clinical trials for this indication when compared to current standard of therapy with similar or less bleeding. Nevertheless, the agents all offer different pharmacological profiles, which have an impact on patient selection and potential advantages in clinical practice.

Topics: Animals; Blood Coagulation; Factor Xa Inhibitors; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Risk Factors; Rivaroxaban; Thiazoles; Thiophenes; Treatment Outcome; Venous Thromboembolism

Four non-vitamin K antagonist oral anticoagulants, apixaban, dabigatran, edoxaban, and rivaroxaban, have been evaluated in phase III clinical trials for the treatment of acute venous thromboembolism, and all except edoxaban have also been studied for extended secondary prophylaxis after venous thromboembolism. Rivaroxaban, and recently also dabigatran, has been approved for this indication, and it is therefore timely to review the characteristics, efficacy, and safety of these drugs with emphasis on patients with venous thromboembolism. This review focuses on the clinical results from the phase III trials, separately for each of the drugs as compared with vitamin K antagonists. We also address the results from meta-analyses that were published recently. Finally, the results in some special groups of interest-renal impairment, elderly patients, and patients with cancer-are reviewed, although they only comprised small minorities of the study populations. All 4 drugs demonstrated noninferiority against vitamin K antagonists in the acute treatment and clear superiority against placebo in the extended treatment (not performed with edoxaban). The risk of bleeding was generally lower with non-vitamin K antagonist oral anticoagulants, and the reduction of risk of intracranial hemorrhage seems to mirror the experience from atrial fibrillation trials. In conclusion, during the past 30 years we have moved from a week of hospitalization and intravenous heparin therapy, via low-molecular-weight heparin injections subcutaneously and early discharge from the hospital, to the possibility of only oral outpatient therapy without coagulation monitoring, yet safe for patients with acute venous thromboembolism.

Topics: Administration, Oral; Animals; Anticoagulants; Clinical Trials, Phase III as Topic; Dabigatran; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Risk Factors; Rivaroxaban; Thiazoles; Time Factors; Treatment Outcome; Venous Thromboembolism

Several new anticoagulants have entered the clinical arena or are under clinical development. These drugs include indirect (fondaparinux) and direct oral factor Xa inhibitors (rivaroxaban, apixaban, edoxaban, betrixaban), and the direct thrombin inhibitor dabigatran. Especially the oral direct FXa and FIIa inhibitors overcome many of the shortcomings of heparins and vitamin K antagonists (VKAs). They are administered orally at a fixed dose; regular monitoring is not necessary; interaction with other drugs or nutrition occur less than with VKAs and they are at least as effective as VKAs for most indications tested. They are associated with about 50 % less intracranial bleeding than VKAs. Nevertheless, they are still associated with bleeding complications. Bleeding can occur spontaneously or as a result of trauma or urgent surgery. In such situations rapid reversal of the anticoagulant effect is highly desirable. For unfractionated heparin protamine, and for VKAs prothrombin complex concentrates are available as specific antidotes. Under clinical development are: for the direct and indirect FXa inhibitors a modified recombinant FXa (andexanet alpha), which lacks enzymatic activity; and for dabigatran a Fab fragment of a monoclonal antibody (idarucizumab). In addition a small molecule (aripazine) has entered phase I clinical trials, which seems to inhibit nearly all anticoagulants but VKAs and argatroban. This review summarises the current options and strategies in development to antagonise anticoagulants with a focus on the status of the development of antidotes for the oral direct FXa and FIIa inhibitors.

Topics: Administration, Oral; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticoagulants; Antithrombins; Benzamides; Clinical Trials as Topic; Dabigatran; Factor Xa; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Hemostatics; Heparin; Humans; Infusions, Parenteral; Intracranial Hemorrhages; Polysaccharides; Protamines; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiazoles; Thrombosis; Vitamin K

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

In the last few years, a new category of anticoagulants have been developed, the non-vitamin K oral anticoagulants (NOACs). The NOACs are of two classes: the direct thrombin inhibitor, namely dabigatran etexilate; and the oral factor Xa inhibitors rivaroxaban, apixaban and edoxaban, which have been proven to be as effective and safe (and sometimes, superior) compared to warfarin in the treatment of both atrial fibrillation (AF) and venous thromboembolism (VTE). One major concern about their use has always been the lack of an effective antidote or reversal strategy. The objective of this editorial is to provide an overview of the characteristics of NOAC antidotes that are in development. Moreover, we review their likely place in the management of NOAC-related bleeding episodes.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; 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

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

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

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thromboembolism; Vitamin K

Although the direct oral anticoagulants (DOACs) do not require routine monitoring and reduce bleeding compared with warfarin, there are special circumstances in which laboratory measurement or reversal of their anticoagulant effect may be indicated. The dilute thrombin time and ecarin-based assays are able to quantify dabigatran across a broad range of concentrations, but are not widely available. A normal thrombin time excludes clinically relevant levels and a normal activated partial thromboplastin time probably excludes excess levels of dabigatran. Factor Xa inhibitors may be quantified with an anti-Xa assay calibrated with drug-specific standards. A normal prothrombin time probably excludes excess levels of rivaroxaban and edoxaban, but not apixaban. Patients with minor and moderate DOAC-associated bleeding can be treated with supportive care and general hemostatic measures. Nonspecific reversal agents (eg, prothrombin complex concentrate, activated prothrombin complex concentrate) are of unproven benefit, carry a risk of thrombosis, and should be reserved for severe bleeding. Specific reversal agents, such as idarucizumab (a monoclonal antibody fragment that binds dabigatran) and andexanet alfa (a recombinant factor Xa variant that binds factor Xa inhibitors but lacks coagulant activity), are in clinical development.

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Anticoagulants; Arginine; Blood Coagulation Factors; Blood Coagulation Tests; Dabigatran; Factor VIIa; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Hemostasis; Humans; Partial Thromboplastin Time; Piperazines; Prothrombin; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiazoles; Thrombin Time

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

New direct oral anticoagulants (NOACs) constitute a novel treatment option for acute venous thromboembolism (VTE), with practical advantages. Individual studies have demonstrated comparable efficacy to that of vitamin K antagonists (VKAs) and have suggested a more favorable safety profile . We performed a meta-analysis to determine the efficacy and safety of NOACs as compared with those of VKAs in patients with acute VTE.. We searched MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and the Clinical Trials Registry up to October 2013. Eligible studies included phase 3 trials comparing NOACs with VKAs in patients with acute VTE. Relative risks (RRs), absolute risk differences and numbers needed to treat (NNTs) to prevent one event were calculated for recurrent VTE, fatal pulmonary embolism (PE), overall mortality, major bleeding, and other bleeding complications, with random-effects models.. Five studies were included, investigating four NOACs (rivaroxaban, dabigatran, apixaban, and edoxaban) in 24 455 patients with acute VTE. RRs for recurrent VTE, fatal PE and overall mortality for NOACs vs. VKAs were 0.88 (95% confidence interval [CI] 0.74-1.05), 1.02 (95% CI 0.39-5.96), and 0.97 (95% CI 0.83-1.14), respectively. The RR for major bleeding was 0.60 (95% CI 0.41-0.88). The NNT with NOACs instead of VKA to prevent one major bleed was 149. The RR and NNT for fatal bleeding were 0.36 (95% CI 0.15-0.87) and 1111. A fixed-effect network analysis did not demonstrate significant differences between individual NOACs and rivaroxaban.. NOACs have comparable efficacy to that of VKAs, and are associated with a significantly lower risk of bleeding complications, although the NNT to prevent one major bleed was relatively high.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Female; Hemorrhage; Humans; Male; Morpholines; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Risk Factors; Rivaroxaban; Thiazoles; Thiophenes; Treatment Outcome; Venous Thromboembolism; Vitamin K

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

Direct oral anticoagulants (DOACs) specifically target factor IIa or Xa and represent a major step forward in the treatment of acute- and long-term prevention of venous thrombo-embolism (VTE). They are at least as effective and as safe as conventional therapy (heparins and vitamin-K inhibitors) and have practical advantages, such as fixed dosing and no need for laboratory monitoring. These antithrombotic agents introduce a new paradigm for the day-to-day management of VTE. Direct oral anticoagulants should streamline the management of most patients with VTE and will facilitate care in the outpatient setting. Nevertheless, it remains uncertain how to select specific DOACs for particular profiles of patients, and the optimal management of bleeding complications is evolving.

Topics: Acute Disease; Administration, Oral; Antithrombins; Benzimidazoles; beta-Alanine; Clinical Trials, Phase III as Topic; Dabigatran; Hemorrhage; Humans; Long-Term Care; Morpholines; Perioperative Care; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Treatment Outcome; Venous Thromboembolism; Vitamin K

Vitamin K antagonists (VKAs) remain the standard therapy for anticoagulation in prevention and treatment of venous thromboembolism (VTE) and for the prevention of stroke in atrial fibrillation (AF). Due to numerous limitations of VKAs, target-specific oral anticoagulants have been developed. Edoxaban is a direct activated factor X inhibitor with attractive features among which are once daily dosing, no need for routine monitoring, and minimal drug-drug interactions. In patients undergoing orthopedic surgery, edoxaban was superior to enoxaparin in preventing VTE. Furthermore, a recent large-scale phase III trial in patients with symptomatic VTE demonstrated that edoxaban was noninferior to warfarin in preventing recurrent VTE and reduced bleeding. In the largest trial of anticoagulation in patients with AF to date, edoxaban was noninferior to warfarin in the prevention of stroke or systemic embolism and reduced bleeding and cardiovascular mortality. This review provides an overview of the pharmacology, clinical trial results, and potential indications for edoxaban.

Topics: Anticoagulants; Atrial Fibrillation; Clinical Trials as Topic; Factor Xa Inhibitors; Hemorrhage; Humans; Pyridines; Randomized Controlled Trials as Topic; Thiazoles; Treatment Outcome; Venous Thrombosis; Warfarin

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

Edoxaban, a factor Xa inhibitor, is a new oral anticoagulant that has been developed as an alternative to vitamin K antagonists. However, its safety remains unexplored.. Medline, Embase and Web of Science were searched to March 8, 2014 for prospective, randomized controlled trials (RCTs) that assessed the safety profile of edoxaban with warfarin. Safety outcomes examined included bleeding risk and mortality.. Five trials including 31,262 patients that met the inclusion criteria were pooled. Overall, edoxaban was associated with a significant decrease in major or clinically relevant nonmajor bleeding events [risk ratio (RR) 0.78, 95% confidence interval (CI) 0.74 to 0.82, p<0.001] and any bleeding events [RR 0.82, 95% CI 0.79 to 0.85, p<0.001]. Edoxaban also showed superiority to warfarin both in all-cause mortality [RR 0.92, 95% CI 0.85 to 0.99, p = 0.02] and cardiovascular mortality [RR 0.87, 95% CI 0.79 to 0.96, p = 0.004]. Subgroup analyses indicated that RRs of edoxaban 30, 60 or 120 mg/d were 0.67 (p<0.001), 0.87 (p<0.001) and 3.3 (p = 0.004) respectively in major or clinically relevant nonmajor bleeding; 0.71 (p<0.001), 0.89 (p<0.001) and 2.29 (p = 0.002) respectively in any bleeding; as well as 0.86 (p = 0.01), 0.87 (p = 0.01) and 0.28 (p = 0.41) respectively in cardiovascular death… Meanwhile, paramount to note that pooled results other than the largest trial showed edoxaban was still associated with a decrease in the rate of major or clinically relevant nonmajor bleeding event (p = 0.02) and any bleeding (p = 0.002), but neither in all-cause death (p = 0.66) nor cardiovascular death (p = 0.70).. Edoxaban, a novel orally available direct factor Xa inhibitor, seems to have a favorable safety profiles with respect to bleeding risk and non-inferior in mortality when compared to warfarin. Further prospective RCTs are urgently needed to confirm the results of this meta-analysis.

Topics: Anticoagulants; Hemorrhage; Humans; Pyridines; Randomized Controlled Trials as Topic; Risk; Thiazoles

Long-term anticoagulation treatment with warfarin has been associated with a number of limitations in clinical practice and there is a need for more convenient long-term anticoagulation treatment. One of the non-vitamin K oral anticoagulants in development is edoxaban, a factor Xa inhibitor that is administered once daily. The pharmacological properties of edoxaban have various advantages in anticoagulant therapy. Edoxaban quickly reaches peak plasma concentrations in 1.5 h, has a half-life of 10-14 h, has relatively high bioavailability of 62% and exhibits highly selective, competitive, concentration-dependent inhibition of human factor Xa. The plasma concentrations of edoxaban are also closely correlated with suppression of thrombin generation and a range of platelet activation parameters (fragment 1+2, thrombin-antithrombin complex, and β-thromboglobulin), which edoxaban has been shown to rapidly inhibit. The anticoagulant activity of edoxaban is not affected by food intake or ethnicity and a number of drug-drug interaction studies have been performed. Co-administration of edoxaban with strong P-glycoprotein inhibitors, such as dronedarone, quinidine, and verapamil requires edoxaban dose-reduction by 50% to avoid the risk of over-exposure. The exposure of edoxaban may also increase in patients with a body weight ≤60 kg and moderate renal impairment. This meant a dose-reduction strategy in patients at risk of over-exposure was utilized in Phase III clinical studies. In conclusion, the pharmacological properties of edoxaban provide rapid and specific inhibition of factor Xa, which is closely related to plasma concentrations. Given the limitations with long-term warfarin therapy, once-daily edoxaban may provide a convenient long-term alternative for patients.

Topics: Administration, Oral; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Drug Evaluation, Preclinical; Drug Interactions; Epidemiologic Methods; Factor Xa Inhibitors; Hemorrhage; Humans; Pyridines; Rabbits; Rats; Thiazoles; Thrombosis

The traditional treatment of venous thromboembolism (VTE) has been use of heparin and vitamin K antagonists (VKA), and although shown to be effective, they have numerous limitations. New oral anticoagulants (NOACs) including direct thrombin (factor IIa) inhibitors (dabigatran) and selective factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) have emerged as promising alternatives with the potential to overcome the limitations of traditional treatments. Clinical trials have been performed with a view to making significant changes to the acute, long-term and extended treatment of VTE. Data are now available on the efficacy and safety, including bleeding rates, of the NOACs in comparison with VKA in the acute treatment and secondary prevention of VTE as well as in comparison with placebo extended VTE treatment. This review compares and contrasts the design and results of the Phase III trials of NOACs in VTE and discusses the implications of the NOACs in terms of treatment strategies in VTE patients.

Topics: Anticoagulants; Clinical Trials, Phase III as Topic; Dabigatran; Hemorrhage; Humans; Outcome Assessment, Health Care; Patient Acuity; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Secondary Prevention; Thiazoles; Venous Thromboembolism

In the last 4 years, 6 phase 3 trials including a total of 27,023 patients with venous thromboembolism (VTE) compared a direct oral anticoagulant (DOAC) with vitamin K antagonists (VKAs). To aid the clinician in assessing the amount of information, we address frequently raised clinical questions in a review of combined trial results. We included the phase 3 trials that compared dabigatran etexilate, rivaroxaban, apixaban, or edoxaban with VKA therapy in patients with acute symptomatic VTE. Recurrent VTE occurred in 2.0% of DOAC recipients compared with 2.2% in VKA recipients (relative risk [RR] 0.90, 95% confidence interval [CI] 0.77-1.06). Treatment with a DOAC significantly reduced the risk of major bleeding (RR 0.61, 95% CI 0.45-0.83). In parallel, intracranial bleeding, fatal bleeding, and clinically relevant nonmajor bleeding occurred significantly less in DOAC recipients. The efficacy and safety of DOACs were consistent in patients with pulmonary embolism, deep venous thrombosis, a body weight ≥100 kg, moderate renal insufficiency, an age ≥75 years, and cancer. In conclusion, DOACs and VKAs have similar efficacy in the treatment of acute symptomatic VTE, a finding that is consistent in key clinical subgroups. Treatment with a DOAC significantly reduces the risks of major bleeding.

Topics: Acute Disease; Administration, Oral; Anticoagulants; Benzimidazoles; Clinical Trials, Phase III as Topic; Dabigatran; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Morpholines; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiazoles; Thiophenes; Venous Thromboembolism; Vitamin K

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

Acute venous thromboembolism (VTE) is a common disease associated to significant morbidity and mortality.. We systematically reviewed and meta-analysed clinical outcomes with direct oral anticoagulants (DOAC: dabigatran, rivaroxaban, apixaban or edoxaban) for treatment of acute VTE. We used MEDLINE and CENTRAL, clinical trials registers, conference proceedings, and websites of regulatory agencies to identify randomised clinical trials of DOAC compared with conventional treatment [parenteral anticoagulant followed by a vitamin K antagonist (VKA)] for acute VTE. Two investigators independently extracted data. Relative risk of recurrent VTE, bleeding events, deaths and a net clinical endpoint (composite of recurrent VTE, major bleeding, and death) were estimated using a random effect meta-analysis (RevMan software).. Six trials including 27,127 patients were selected. The risk of recurrent VTE was similar with the DOAC and standard treatment (relative risk 0.91, 95% confidence interval 0.79 to 1.06). The DOAC reduced the risk of major bleeding in comparison with standard treatment (0.62, 0.45 to 0.85) (absolute risk difference, -0.6%; 95% confidence interval -1.0% to -0.3%), but there was heterogeneity across trials in the relative risk of bleeding. No between treatment differences were found in the relative risk of all-cause mortality (0.98, 0.84 to 1.14). The DOAC and conventional treatment differed on the net clinical endpoint (0.85, 0.75 to 0.97). Subgroup analyses in relevant subgroups (index pulmonary embolism, heparin lead-in, age, gender, renal function, presence of cancer), as well as sensitivity analyses, were consistent with the main analysis.. The DOAC seem as effective as, and probably safer than standard treatment of acute VTE. The relative efficacy and safety of the DOAC was consistent across a wide range of patients.

Topics: Administration, Oral; Animals; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Venous Thromboembolism

New oral factor Xa inhibitors are intended to progressively substitute the oral vitamin K antagonists and parenteral indirect inhibitors of factor Xa in the prevention and treatment of venous and arterial thromboembolic episodes. This article focuses on the main clinical studies and on biological measurements of new oral factor Xa inhibitors, and addresses several safety issues. These newer agents do not require any routine laboratory monitoring of blood coagulation; however, biological tests have been developed in order to assess the plasma concentration of these drugs in several clinical settings. This article reviews these 4 oral direct factor Xa inhibitors.

Topics: Administration, Oral; Benzamides; Blood Coagulation Tests; Drug Monitoring; Factor Xa Inhibitors; Hemorrhage; Humans; Morpholines; Precision Medicine; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes

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

The direct thrombin inhibitor dabigatran and factor Xa inhibitors rivaroxaban and apixaban are US Food and Drug Administration (FDA)-approved target-specific oral anticoagulants (TSOACs) that have emerged onto the market for use in some indications similar to those for warfarin; in addition, edoxaban is seeking FDA approval. Similar indications include reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation for all 3 agents, for the prevention of deep vein thrombosis that may lead to pulmonary embolism in patients undergoing hip or knee surgery for rivaroxaban and apixaban, and for the treatment and prevention of deep vein thrombosis and pulmonary embolism. As anticoagulants, they are all associated with a risk of bleeding, and, unfortunately, there are no approved antidotes for reversal of these agents. A number of small studies in human subjects and in human/animal models exposed to TSOACs have evaluated the use of activated charcoal, hemodialysis for dabigatran, or clotting factor concentrates for their ability to neutralize the anticoagulant effects or reduce drug concentrations of TSOACs. Clotting factor concentrates that have been used include prothrombin complex concentrates and recombinant factor VII. This review examines studies and case reports evaluating these strategies for expedited or emergent reversal of TSOACs.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Blood Coagulation Factors; Charcoal; Dabigatran; Factor VIIa; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Renal Dialysis; Rivaroxaban; Thiazoles; Thiophenes

Disadvantages with traditional anticoagulants (vitamin K antagonists and heparinoids) have led to the development on non-vitamin K antagonist oral anticoagulants (NOACs). These agents are set to replace the traditional anticoagulants in situations such as following orthopaedic surgery, in atrial fibrillation, and in the prevention and treatment of venous thromboembolism. Although superior to vitamin K antagonists and heparinoids in several aspects, NOACs retain the ability to cause haemorrhage and, despite claims to the contrary, may need monitoring. This review aims to summarise key aspects of the NOACs of relevance to the laboratory.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Dose-Response Relationship, Drug; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Thrombosis; Treatment Outcome; Vitamin K

In the past decade, several new oral anticoagulants (NOACs) have been studied and approved for the prophylaxis and treatment of arterial and venous thromboembolism. These agents were shown to be as effective as or better than warfarin and resulted in comparable or lower bleeding rates than warfarin. Specific antidotes for the reversal of the anticoagulant effect of these drugs, such as monoclonal antibodies against the direct thrombin inhibitor dabigatran or recombinant Xa-analog in the case of factor Xa inhibitors, are still being investigated in early clinical trials. In certain situations, as in case of emergency surgery or life-threatening major bleeding, a rapid reversal strategy is needed. Several non-specific prohemostatic agents or coagulation factor concentrates have been suggested as potential candidates for the reversal of NOACs, but the evidence supporting these agents was mainly derived from small animal studies, or is based on partial or complete correction of laboratory parameters in healthy volunteers treated with these agents. Activated prothrombin complex concentrate seems promising for the reversal of dabigatran, while non-activated prothrombin complex concentrates have potential for the reversal of anti-factor Xa. The risk of thromboembolic complications requires careful evaluation. In this article, the evidence- or the lack of it - supporting the use of the different prohemostatic agents for the management of bleeding and for reversal of the different classes of NOACs is discussed.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Blood Coagulation Factors; Dabigatran; Drug Administration Schedule; Hemorrhage; Hemostatics; Humans; Morpholines; Prothrombin; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiazoles; Thiophenes; Thromboembolism

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

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

Andexanet alfa is a modified recombinant inactive factor Xa (FXa) designed to reverse FXa inhibitors. ANNEXA-4 (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) was a multicenter, prospective, phase-3b/4, single-group cohort study that evaluated andexanet alfa in patients with acute major bleeding. The results of the final analyses are presented.. Patients with acute major bleeding within 18 hours of FXa inhibitor administration were enrolled. Co-primary end points were anti-FXa activity change from baseline during andexanet alfa treatment and excellent or good hemostatic efficacy, defined by a scale used in previous reversal studies, at 12 hours. The efficacy population included patients with baseline anti-FXa activity levels above predefined thresholds (≥75 ng/mL for apixaban and rivaroxaban, ≥40 ng/mL for edoxaban, and ≥0.25 IU/mL for enoxaparin; reported in the same units used for calibrators) who were adjudicated as meeting major bleeding criteria (modified International Society on Thrombosis and Haemostasis definition). The safety population included all patients. Major bleeding criteria, hemostatic efficacy, thrombotic events (stratified by occurring before or after restart of either prophylactic [ie, a lower dose, for prevention rather than treatment] or full-dose oral anticoagulation), and deaths were assessed by an independent adjudication committee. Median endogenous thrombin potential at baseline and across the follow-up period was a secondary outcome.. There were 479 patients enrolled (mean age, 78 years; 54% male; 86% White); 81% were anticoagulated for atrial fibrillation, and the median time was 11.4 hours since last dose, with 245 (51%) on apixaban, 176 (37%) on rivaroxaban, 36 (8%) on edoxaban, and 22 (5%) on enoxaparin. Bleeding was predominantly intracranial (n=331 [69%]) or gastrointestinal (n=109 [23%]). In evaluable apixaban patients (n=172), median anti-FXa activity decreased from 146.9 ng/mL to 10.0 ng/mL (reduction, 93% [95% CI, 94-93]); in rivaroxaban patients (n=132), it decreased from 214.6 ng/mL to 10.8 ng/mL (94% [95% CI, 95-93]); in edoxaban patients (n=28), it decreased from 121.1 ng/mL to 24.4 ng/mL (71% [95% CI, 82-65); and in enoxaparin patients (n=17), it decreased from 0.48 IU/mL to 0.11 IU/mL (75% [95% CI, 79-67]). Excellent or good hemostasis occurred in 274 of 342 evaluable patients (80% [95% CI, 75-84]). In the safety population, thrombotic events occurred in 50 (10%) patients; in 16 patients, these occurred during treatment with prophylactic anticoagulation that began after the bleeding event. No thrombotic episodes occurred after oral anticoagulation restart. Specific to certain populations, reduction of anti-FXa activity from baseline to nadir significantly predicted hemostatic efficacy in patients with intracranial hemorrhage (area under the receiver operating characteristic curve, 0.62 [95% CI, 0.54-0.70]) and correlated with lower mortality in patients <75 years of age (adjusted. In patients with major bleeding associated with the use of FXa inhibitors, treatment with andexanet alfa reduced anti-FXa activity and was associated with good or excellent hemostatic efficacy in 80% of patients.. URL: https://www.. gov; Unique identifier: NCT02329327.

Topics: Aged; Anticoagulants; Cohort Studies; Enoxaparin; Factor Xa; Factor Xa Inhibitors; Female; Hemorrhage; Hemostatics; Humans; Male; Prospective Studies; Recombinant Proteins; Rivaroxaban; Thrombin; Thrombosis

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

The optimal duration of anticoagulation therapy for isolated distal deep vein thrombosis in patients with cancer is clinically relevant, but the evidence is lacking. The prolonged anticoagulation therapy could have a potential benefit for prevention of thrombotic events; however, it could also increase the risk of bleeding.. In a multicenter, open-label, adjudicator-blinded, randomized clinical trial at 60 institutions in Japan, we randomly assigned patients with cancer with isolated distal deep vein thrombosis, in a 1-to-1 ratio, to receive either a 12-month or 3-month edoxaban treatment. The primary end point was a composite of a symptomatic recurrent venous thromboembolism (VTE) or VTE-related death at 12 months. The major secondary end point was major bleeding at 12 months, according to the criteria of the International Society on Thrombosis and Haemostasis. The primary hypothesis was that a 12-month edoxaban treatment was superior to a 3-month edoxaban treatment with respect to the primary end point.. From April 2019 through June 2022, 604 patients were randomized, and after excluding 3 patients who withdrew consent, 601 patients were included in the intention-to-treat population: 296 patients in the 12-month edoxaban group and 305 patients in the 3-month edoxaban group. The mean age was 70.8 years, 28% of the patients were men, and 20% of the patients had symptoms of deep vein thrombosis at baseline. The primary end point of a symptomatic recurrent VTE event or VTE-related death occurred in 3 of the 296 patients (1.0%) in the 12-month edoxaban group and in 22 of the 305 patients (7.2%) in the 3-month edoxaban group (odds ratio, 0.13; 95% CI, 0.03-0.44). The major secondary end point of major bleeding occurred in 28 of the 296 patients (9.5%) in the 12-month edoxaban group and in 22 of the 305 patients (7.2%) in the 3-month edoxaban group (odds ratio, 1.34; 95% CI, 0.75-2.41). The prespecified subgroups did not affect the estimates on the primary end point.. In patients with cancer with isolated distal deep vein thrombosis, 12 months was superior to 3 months for an edoxaban treatment with respect to the composite outcome of a symptomatic recurrent VTE or VTE-related death.. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03895502.

Topics: Aged; Anticoagulants; Female; Hemorrhage; Humans; Male; Neoplasms; Thrombosis; Venous Thromboembolism; Venous Thrombosis

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

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

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

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

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

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

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

Topics: Aged; Anticoagulants; Atrial Fibrillation; Cardiovascular Diseases; Factor Xa Inhibitors; Female; Hemorrhage; Hospitalization; Humans; Male; Middle Aged; Pyridines; Risk Assessment; Risk Factors; Thiazoles; Time Factors; Treatment Outcome; Warfarin

Atrial fibrillation (AF) is common in older people with frailty and is associated with an increased risk of stroke and systemic embolism. Whilst oral anticoagulation is associated with a reduction in this risk, there is a lack of data on the safety and efficacy of direct oral anticoagulants (DOACs) in people with frailty. This study aims to report clinical outcomes of patients with AF in the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial by frailty status.. Post hoc analysis of 20,867 participants in the ENGAGE AF-TIMI 48 trial, representing 98.8% of those randomised. This double-blinded double-dummy trial compared two once-daily regimens of edoxaban (a DOAC) with warfarin. Participants were categorised as fit, living with pre-frailty, mild-moderate, or severe frailty according to a standardised index, based upon the cumulative deficit model. The primary efficacy endpoint was stroke or systemic embolism and the safety endpoint was major bleeding.. A fifth (19.6%) of the study population had frailty (fit: n = 4459, pre-frailty: n = 12,326, mild-moderate frailty: n = 3722, severe frailty: n = 360). On average over the follow-up period, the risk of stroke or systemic embolism increased by 37% (adjusted HR 1.37, 95% CI 1.19-1.58) and major bleeding by 42% (adjusted HR 1.42, 1.27-1.59) for each 0.1 increase in the frailty index (four additional health deficits). Edoxaban was associated with similar efficacy to warfarin in every frailty category, and a lower risk of bleeding than warfarin in all but those living with severe frailty.. Edoxaban was similarly efficacious to warfarin across the frailty spectrum and was associated with lower rates of bleeding except in those with severe frailty. Overall, with increasing frailty, there was an increase in stroke and bleeding risk. There is a need for high-quality, frailty-specific population randomised control trials to guide therapy in this vulnerable population.. ClinicalTrials.gov NCT00781391 . First registered on 28 October 2008.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Double-Blind Method; Drug Administration Schedule; Factor Xa Inhibitors; Female; Follow-Up Studies; Frailty; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Prognosis; Pyridines; Thiazoles; Treatment Outcome; Warfarin

The KYU-RABLE study, a prospective, multicenter, single-arm interventional study, evaluated the efficacy and safety of uninterrupted oral edoxaban in patients undergoing catheter ablation (CA) for atrial fibrillation (AF).Methods and Results:We enrolled patients with AF from 23 centers in Japan. Edoxaban 60 mg (30 mg in patients indicated for dose adjustment) was administered uninterrupted, once daily in the morning for ≥4 weeks before CA and 4 weeks ±7 days after CA with one dose delayed on the procedural day. The primary endpoint was a composite of thromboembolism and major bleeding during 4 weeks from the procedural day. Among the 513 eligible patients who underwent CA, 63.5% received edoxaban 60 mg/day and 36.1% received 30 mg/day. For the primary endpoint, no thromboembolism and 1 major bleeding event (0.2%, cardiac tamponade) were observed. The plasma edoxaban concentration decreased depending on the time from the last administration to the CA procedure. However, plasma levels of coagulative biomarkers were within appropriate ranges regardless of the interval from the last administration of edoxaban.. The present study provided evidence of the efficacy and safety of uninterrupted edoxaban administered once daily in the morning, with one dose delayed on procedural day, in patients with AF undergoing CA. Edoxaban was associated with a low risk of periprocedural thromboembolic and bleeding complications.

Topics: Administration, Oral; Aged; Atrial Fibrillation; Blood Coagulation; Catheter Ablation; Drug Administration Schedule; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Japan; Male; Middle Aged; Prospective Studies; Pyridines; Risk Factors; Thiazoles; Thromboembolism; Time Factors; Treatment Outcome

Numerous scales exist for the classification of major bleeding events. Limited data compare the most commonly used bleeding scales within a single at-risk cohort of patients with atrial fibrillation. Here, we analyze bleeding outcomes according to the ISTH (International Society on Thrombosis and Hemostasis), TIMI (Thrombolysis in Myocardial Infarction), GUSTO (Global Usage of Strategies to Open Occluded Arteries), and BARC (Bleeding Academic Research Consortium) bleeding scales in the ENGAGE AF (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation)-TIMI 48 trial (NCT00781391) of edoxaban versus warfarin.. A total of 10 311 bleeding events were reported. In a comparison of the most severe events in each scale, ISTH major bleeding was the most common (n=1289), followed by TIMI major (n=548), GUSTO severe/life-threatening (n=347), and BARC 3c+5 (n=276) bleeding. Lower bleeding risk with edoxaban compared with warfarin was seen regardless of bleeding scale (higher-dose edoxaban regimen range: hazard ratio [HR], 0.47 [95% CI, 0.35-0.62] for BARC 3c+5 versus HR, 0.80 [95% CI, 0.71-0.91] for ISTH major; lower-dose edoxaban regimen range: HR, 0.32 [95% CI, 0.23-0.45] for BARC 3c+5 versus HR, 0.47 [95% CI, 0.41-0.55] for ISTH major). Furthermore, a gradient of more pronounced risk reduction with edoxaban was observed with greater severity of first bleeding event (higher-dose edoxaban regimen: HR, 0.47 [95% CI, 0.35-0.62] for BARC 3c+5 bleeds versus HR, 0.86 [95% CI, 0.81-0.91] for any BARC bleed; lower-dose edoxaban regimen: HR, 0.32 [95% CI, 0.23-0.45] for BARC 3c+5 bleeds versus HR, 0.68 [95% CI, 0.63-0.72] for any BARC bleed). The direction of this trend was consistent for both gastrointestinal bleeding and nongastrointestinal bleeding.. Among patients with atrial fibrillation at risk for stroke, there was a >4-fold difference in the frequency of the most severe bleeding events across commonly used bleeding scales. Furthermore, the relative safety of edoxaban compared with warfarin tended to increase with greater severity of bleeding.. URL: https://www.clinicaltrials.gov. Unique identifier: NCT00781391.

Topics: Aged; Atrial Fibrillation; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Middle Aged; Pyridines; Risk Factors; Thiazoles; Warfarin

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

ETNA-VTE-Japan is an ongoing prospective observational study conducted as part of a postmarketing observational study to investigate the safety and effectiveness of edoxaban in Japanese patients for whom the drug has been newly prescribed to treat venous thromboembolism (VTE) and prevent VTE recurrence. The results of an interim analysis of data collected at 3 months are presented.Methods and Results:A total of 1,732 patients were enrolled. The safety and effectiveness analyses included data from 1,703 and 1,699 patients, respectively. In the safety analysis set, 39.4% of patients were aged ≥75 years, 58.2% had body weight ≤60 kg, and 22.2% had creatinine clearance <50 mL/min. Approximately 90% of patients received a dose in accordance with the package insert. Approximately 80% of patients continued treatment; the mean treatment period was 74.5 days. The incidence of bleeding adverse events and major bleeding was 6.3% and 1.4%, respectively. The incidence of VTE recurrence and symptomatic VTE recurrence in the on-treatment population was 0.8% and 0.4%, respectively. Safety and effectiveness profiles of edoxaban in patients receiving the low dose (30 mg/day), generally administered to patients with high bleeding risk, were similar to those of the standard dose (60 mg/day).. The results confirm no major concerns about the safety and effectiveness of edoxaban in Japanese patients with VTE in the first 3 months of treatment. (Trial registration No.: UMIN000016387.).

Topics: Aged; Aged, 80 and over; Female; Hemorrhage; Humans; Incidence; Japan; Male; Middle Aged; Product Surveillance, Postmarketing; Pyridines; Thiazoles; Venous Thromboembolism

Patients with active cancer and venous thromboembolism (VTE) are at high risk of recurrence. Therefore, continued anticoagulant therapy beyond the initial 6 months is suggested in this patient population, but evidence supporting this approach is limited.. The Hokusai VTE Cancer trial compared edoxaban with dalteparin for VTE treatment in patients with active cancer. This post hoc analysis focused on the follow-up period from 6 to 12 months. The primary outcome was the composite of adjudicated first recurrent VTE or major bleeding. Secondary outcomes included recurrent VTE, major bleeding, and clinically relevant bleeding.. Of the 522 and 524 patients randomized to edoxaban or dalteparin, 294 (56%) received edoxaban and 273 (52%) received dalteparin for more than 6 months (median duration of 318 and 211 days, respectively). Between 6 and 12 months, the primary outcome during study treatment occurred in seven patients (2.4%) in the edoxaban group and six patients (2.2%) in the dalteparin group (unadjusted hazard ratio 1.05; 95% confidence interval, 0.36-3.05). Recurrent VTE occurred in two patients (0.7%) in the edoxaban group and in three patients (1.1%) in the dalteparin group, whereas major bleeding occurred in 5 (1.7%) and three patients (1.1%), respectively.. The rates of recurrent VTE or major bleeding are relatively low among patients with active cancer receiving extended anticoagulant therapy beyond 6 months. Extended treatment with oral edoxaban appears as effective and safe as subcutaneous dalteparin.

Topics: Aged; Blood Coagulation; Dalteparin; Drug Administration Schedule; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Incidence; Male; Middle Aged; Neoplasms; Prospective Studies; Pulmonary Embolism; Pyridines; Recurrence; Risk Factors; Thiazoles; Time Factors; Treatment Outcome; Venous Thromboembolism; Venous Thrombosis

An analysis of the activated partial thromboplastin time (APTT) in major orthopedic surgery patients receiving edoxaban for the prevention of venous thromboembolism (VTE) was carried out.. The APTT waveform was analyzed in the above patients to monitor edoxaban administration.. Of these 99 patients, 12 exhibited deep vein thrombosis, and 25 had massive bleeding. An increased biphasic pattern of the APTT waveform was observed after the administration of edoxaban, but there were no significant differences between the patients with and without complications. The peak times of acceleration, velocity, and 1/2 fibrin formation were significantly prolonged after the administration of edoxaban, especially in patients with massive bleeding, and were moderately correlated with the anti-Xa activity. While the heights of velocity and acceleration peak 2 were lower in patients receiving warfarin treatment than in those receiving edoxaban, the widths of these parameters were significantly longer. The height of 1/2 fibrin formation and the width of acceleration peaks 1 and 2 and the velocity were significantly increased after the administration of edoxaban.. The peak time of the APTT waveform was significantly prolonged after the administration of edoxaban. The analysis of the APTT waveform may therefore be useful for the prediction of the risk of massive bleeding.

Topics: Aged; Drug Monitoring; Hemorrhage; Humans; Male; Middle Aged; Orthopedic Procedures; Partial Thromboplastin Time; Pyridines; Thiazoles; Venous Thromboembolism; Venous Thrombosis

Low-molecular-weight heparin is the standard treatment for cancer-associated venous thromboembolism. The role of treatment with direct oral anticoagulant agents is unclear.. In this open-label, noninferiority trial, we randomly assigned patients with cancer who had acute symptomatic or incidental venous thromboembolism to receive either low-molecular-weight heparin for at least 5 days followed by oral edoxaban at a dose of 60 mg once daily (edoxaban group) or subcutaneous dalteparin at a dose of 200 IU per kilogram of body weight once daily for 1 month followed by dalteparin at a dose of 150 IU per kilogram once daily (dalteparin group). Treatment was given for at least 6 months and up to 12 months. The primary outcome was a composite of recurrent venous thromboembolism or major bleeding during the 12 months after randomization, regardless of treatment duration.. Of the 1050 patients who underwent randomization, 1046 were included in the modified intention-to-treat analysis. A primary-outcome event occurred in 67 of the 522 patients (12.8%) in the edoxaban group as compared with 71 of the 524 patients (13.5%) in the dalteparin group (hazard ratio, 0.97; 95% confidence interval [CI], 0.70 to 1.36; P=0.006 for noninferiority; P=0.87 for superiority). Recurrent venous thromboembolism occurred in 41 patients (7.9%) in the edoxaban group and in 59 patients (11.3%) in the dalteparin group (difference in risk, -3.4 percentage points; 95% CI, -7.0 to 0.2). Major bleeding occurred in 36 patients (6.9%) in the edoxaban group and in 21 patients (4.0%) in the dalteparin group (difference in risk, 2.9 percentage points; 95% CI, 0.1 to 5.6).. Oral edoxaban was noninferior to subcutaneous dalteparin with respect to the composite outcome of recurrent venous thromboembolism or major bleeding. The rate of recurrent venous thromboembolism was lower but the rate of major bleeding was higher with edoxaban than with dalteparin. (Funded by Daiichi Sankyo; Hokusai VTE Cancer ClinicalTrials.gov number, NCT02073682 .).

Topics: Adult; Aged; Anticoagulants; Dalteparin; Follow-Up Studies; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Intention to Treat Analysis; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasms; Pyridines; Recurrence; Thiazoles; Venous Thromboembolism

Cancer patients with venous thromboembolism (VTE) have a two- to six-fold increased risk of anticoagulant-related major bleeding events compared with VTE patients without cancer. It is unknown whether major bleeding events are more severe in cancer patients than in those without cancer. Individual patient data from four randomized phase III trials that compared factor Xa inhibitors and vitamin K antagonists for the treatment of VTE were used to compare the severity of major bleeding events in patients with and without cancer. Using predefined criteria, the severity of the clinical presentation and course of major bleeding events were classified into four categories of increasing severity. A one-stage meta-analysis was used to evaluate the effect of cancer on the severity of the clinical presentation and course by estimating crude odds ratios (ORs) and ORs adjusted for age, sex and anticoagulant type with 95% confidence intervals (CIs). The study group comprised 290 patients with major bleeding, of whom 50 (17%) had cancer. The clinical presentation was judged to be severe (category 3 or 4) in 38% of patients with cancer and 44% of patients without cancer (adjusted OR, 0.90; 95% CI, 0.47-1.72). The clinical course was found to be severe in 20 and 25% of patients with and without cancer, respectively (adjusted OR, 0.75; 95% CI, 0.35-1.61). The present study suggests that the clinical presentation and course of anticoagulant-related major bleeding events are not more severe in cancer patients than in patients without cancer. This may be reassuring for physicians who treat cancer patients with anticoagulant-related bleeding.

Topics: Aged; Anticoagulants; Blood Transfusion; Double-Blind Method; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Neoplasms; Odds Ratio; Prospective Studies; Pyridines; Rivaroxaban; Thiazoles; Venous Thromboembolism

To report a randomized study that investigated the safety (risk of major bleeds) and potential efficacy of edoxaban, an oral anticoagulant that targets the major components of arterial thrombi, to prevent loss of patency following endovascular treatment (EVT).. Between February 2012 and June 2014, 203 patients who underwent femoropopliteal EVT were randomized to receive aspirin plus edoxaban or aspirin plus clopidogrel for 3 months in the Edoxaban in Peripheral Arterial Disease (ePAD) study ( ClinicalTrials.gov identifier NCT01802775). Randomization assigned 101 patients (mean age 68.0±10.4 years; 67 men) to the edoxaban group and 102 patients (mean age 66.7±8.6 years; 78 men) to the clopidogrel group. The primary safety endpoint was bleeding as classified by the TIMI (Thrombolysis in Myocardial Infarction) criteria and ISTH (International Society of Thrombosis and Hemostasis) criteria; the efficacy endpoint was the rate of restenosis/reocclusion.. There were no major or life-threatening bleeding events in the edoxaban group, while there were 2 major and 2 life-threatening bleeding events in the clopidogrel group by the TIMI criteria. By the ISTH classification, there was 1 major and 1 life-threatening bleeding event vs 5 major and 2 life-threatening bleeding events, respectively [relative risk (RR) 0.20, 95% confidence interval (CI) 0.02 to 1.70]. The bleeding risk was not statistically different with either treatment when assessed by TIMI or ISTH. Following 6 months of observation, there was a lower incidence of restenosis/reocclusion with edoxaban compared with clopidogrel (30.9% vs 34.7%; RR 0.89, 95% CI 0.59 to 1.34, p=0.643).. These results suggest that patients who have undergone EVT have similar risks for major and life-threatening bleeding events with edoxaban and aspirin compared with clopidogrel and aspirin. The incidence of restenosis/reocclusion events, while not statistically different, was lower with edoxaban and aspirin, but an adequately sized trial will be needed to confirm these findings.

Topics: Aged; Aspirin; Clopidogrel; Drug Therapy, Combination; Endovascular Procedures; Europe; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Hemorrhage; Humans; Israel; Lower Extremity; Male; Middle Aged; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Proof of Concept Study; Prospective Studies; Pyridines; Recurrence; Risk Factors; Thiazoles; Thrombosis; Time Factors; Treatment Outcome; United States; Vascular Patency

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

The EdoxabaN vs. warfarin in subjectS UndeRgoing cardiovErsion of atrial fibrillation (ENSURE-AF) (NCT02072434) study was a multicentre prospective, randomized, open-label, blinded-endpoint evaluation (PROBE) trial comparing edoxaban with enoxaparin/warfarin followed by warfarin alone in 2199 non-valvular atrial fibrillation patients undergoing electrical cardioversion and showed comparable rates of bleeding and thromboembolism between treatments. This prespecified ancillary analysis investigated the impact of edoxaban therapy on treatment satisfaction and utilization of healthcare services.. The Perception of Anticoagulant Treatment Questionnaire (PACT-Q2) was completed by study patients on Day 28 post-cardioversion. Higher scores represent greater satisfaction. Healthcare resource utilizations were collected from randomization to Day 28 post-cardioversion. Data from patients who received at least one dose of study drugs were analysed. Patients treated with edoxaban were more satisfied than enoxaparin/warfarin in both PACT-Q treatment satisfaction and convenience scores (P < 0.001 for both). Differences in treatment satisfaction scores were greater in patients who underwent non-transoesophageal echocardiography (TOE)-guided cardioversion than in patients who underwent TOE-guided cardioversion. Edoxaban was associated with fewer clinic visits (4.75 visits vs. 7.60 visits; P < 0.001) and fewer hospital days (3.43 days vs. 5.41 days; P < 0.05). Rates of hospitalizations and emergency room visits were not significantly different. Overall, edoxaban therapy was estimated to reduce healthcare costs by €107.73, €437.92, €336.75, and $246.32 per patient in German, Spanish, Italian, and US settings, respectively.. The convenience of edoxaban therapy over warfarin in patients undergoing cardioversion may provide greater treatment satisfaction and cost savings to the healthcare system.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Cost Savings; Cost-Benefit Analysis; Drug Costs; Echocardiography, Transesophageal; Electric Countershock; Emergency Service, Hospital; Europe; Factor Xa Inhibitors; Female; Hemorrhage; Hospital Costs; Humans; Male; Middle Aged; Patient Readmission; Patient Satisfaction; Pyridines; Risk Factors; Thiazoles; Time Factors; 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

In the Hokusai VTE Cancer study, edoxaban was non-inferior to dalteparin for the composite outcome of recurrent venous thromboembolism (VTE) and major bleeding in 1,050 patients with cancer-associated VTE. The absolute rate of recurrent VTE was 3.4% lower with edoxaban, whereas the absolute rate of major bleeding was 2.9% higher. The present analysis focuses on the sites, clinical presentation, course and outcome of bleeding events, and the associated tumour types. Major bleeds and their severity (categories 1-4) were blindly adjudicated by a committee using a priori defined criteria, and data were analysed in the safety population. Major bleeding occurred in 32 of 522 patients given edoxaban (median treatment duration, 211 days) and in 16 of 524 patients treated with dalteparin (median treatment duration, 184 days); no patients had more than one major bleed. There were no fatal bleeds with edoxaban, and two with dalteparin. Severe bleeding at presentation (category 3 or 4) occurred in 10 (1.9%) and 11 (2.1%) patients in the edoxaban and dalteparin groups, respectively. The excess of major bleeding with edoxaban was confined to patients with gastrointestinal cancer. However, severe major bleeding at presentation (category 3 or 4) in this sub-group occurred in 5 of 165 (3.0%) and in 3 of 140 (2.1%) patients given edoxaban or dalteparin, respectively.In conclusion, this analysis suggests that while oral edoxaban is an appropriate alternative to subcutaneous dalteparin for treatment of cancer-associated VTE, the use of edoxaban in patients with gastrointestinal cancer requires careful benefit-risk weighting.

Topics: Aged; Anticoagulants; Clinical Decision-Making; Dalteparin; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Neoplasms; Patient Selection; Pyridines; Recurrence; Risk Assessment; Risk Factors; Severity of Illness Index; Thiazoles; Time Factors; Treatment Outcome; Venous Thromboembolism

Sudden death in patients with severe motor and intellectual disabilities (SMID) is sometimes caused in part by pulmonary thromboembolism (PTE), and deep venous thrombosis (DVT) has drawn attention as a possible embolic source. Warfarin, which is a conventional therapeutic agent, is not easy to control appropriately, and daily management can be especially difficult in SMID patients. On the other hand, edoxaban tosilate hydrate, which has been newly approved for insurance coverage for the treatment of DVT, is not listed in the Guidelines for the Diagnosis, Treatment and Prevention of Pulmonary Thromboembolism and Deep Vein Thrombosis (DVT-PTE guidelines). The aim of this study is to evaluate the efficacy and safety of anticoagulation therapy (warfarin vs. edoxaban) in DVT treatment in SMID patients by means of an open-label, randomized controlled trial. The primary endpoint is the incidence of hemorrhagic events during 12 months of follow up.

Topics: Anticoagulants; Factor Xa Inhibitors; Hemorrhage; Humans; Intellectual Disability; Intelligence; Japan; Motor Activity; Motor Disorders; Multicenter Studies as Topic; Persons with Mental Disabilities; Pyridines; Randomized Controlled Trials as Topic; Thiazoles; Time Factors; Treatment Outcome; Venous Thrombosis; Warfarin

The aim of this study was to investigate whether genetic variants can identify patients with venous thromboembolism (VTE) at an increased risk of bleeding with warfarin.. Hokusai-venous thromboembolism (Hokusai VTE), a randomised, multinational, double-blind, non-inferiority trial, evaluated the safety and efficacy of edoxaban versus warfarin in patients with VTE initially treated with heparin. In this subanalysis of Hokusai VTE, patients genotyped for variants in. The analysis included 47.7% (3956/8292) of the patients in Hokusai VTE. Among 1978 patients randomised to warfarin, 63.0% (1247) were normal responders, 34.1% (675) were sensitive responders and 2.8% (56) were highly sensitive responders. Compared with normal responders, sensitive and highly sensitive responders had heparin therapy discontinued earlier (p<0.001), had a decreased final weekly warfarin dose (p<0.001), spent more time overanticoagulated (p<0.001) and had an increased bleeding risk with warfarin (sensitive responders HR 1.38 [95% CI 1.11 to 1.71], p=0.0035; highly sensitive responders 1.79 [1.09 to 2.99]; p=0.0252).. In this study,. NCT00986154.

Topics: Adult; Aged; Anticoagulants; Blood Coagulation; Cytochrome P-450 CYP2C9; Double-Blind Method; Drug Monitoring; Factor Xa Inhibitors; Female; Genetic Predisposition to Disease; Hemorrhage; Humans; Male; Middle Aged; Pharmacogenetics; Pharmacogenomic Variants; Phenotype; Pyridines; Risk Assessment; Risk Factors; Thiazoles; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K Epoxide Reductases; Warfarin

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

The purpose of this study was twofold: to investigate whether edoxaban significantly decreases the rate of venous thromboembolism (VTE) following closed-wedge high tibial osteotomy (CWHTO), in terms of phlebographic event, and to determine whether edoxaban is safe or increases the rate of hemorrhagic complications. We hypothesized that edoxaban would decrease the incidence of VTE and would not increase the rate of hemorrhagic complications.. We randomly enrolled 60 patients undergoing CWHTO. The patients were divided into two groups: one group receiving edoxaban (15mg in 5 patients, 30mg in 23 patients) and a non-edoxaban group. All patients underwent computed tomography venography on day 7to diagnose postoperative VTE. Blood samples were obtained on the day before CWHTO and on postoperative days 1, 3, 7 and 14. The incidence of VTE and hemorrhagic events in both groups was compared using unpaired Student t-test or chi-square test.. The incidence of VTE was significantly greater in the non-edoxaban group (31.3% versus 7.1%; P=0.02). The incidence of deep vein thrombosis (DVT) was also significantly greater in the non-edoxaban group (28.1% versus 3.6%; P=0.01). A single patient from the edoxaban group experienced major bleeding. On days 3 and 7, D-dimer levels were significantly lower in the edoxaban group (P=0.03 and 0.003, respectively). On days 3, 7 and 14, activated partial thromboplastin time was significantly greater in the edoxaban group (P=0.02, 0.01 and 0.006, respectively).. Patients undergoing CWHTO are at risk of postoperative VTE. Edoxaban helps prevent asymptomatic phlebographic VTE and DVT following CWHTO; however, the risk of major bleeding must be considered.. II.

Topics: Aged; Factor Xa Inhibitors; Female; Fibrin Fibrinogen Degradation Products; Hemorrhage; Humans; Male; Middle Aged; Osteotomy; Partial Thromboplastin Time; Phlebography; Postoperative Complications; Postoperative Period; Prospective Studies; Pyridines; Thiazoles; Tibia; Tomography, X-Ray Computed; Venous Thromboembolism; Venous Thrombosis

Direct oral anticoagulants (DOACs) facilitate the outpatient treatment of venous thromboembolism (VTE). However, the pivotal trials of DOACs have not reported outcomes separately for patients managed either as outpatients or in the hospital. We performed a subgroup analysis of the Hokusai-VTE study comparing efficacy and safety of edoxaban with warfarin in 8,292 patients with acute VTE. Patients received initial therapy with open-label enoxaparin or unfractionated heparin for ≥5 days in the hospital or as an outpatient at the discretion of the treating physician. Edoxaban or warfarin was then given for 3 to 12 months. The primary efficacy outcome was the cumulative incidence of symptomatic recurrent VTE at 12 months. The principal safety outcome was the incidence of clinically relevant bleeding (composite of major or clinically relevant non-major bleeding). Of the 5,223 consecutively enrolled patients with recorded hospital status and length of stay, 1,414 patients (27.1%) were managed as outpatients and 3,809 were managed in hospital. Among the outpatients, initial presentation was symptomatic deep-vein thrombosis (DVT) in 1,183 patients (83.7%) and pulmonary embolism (PE) in 231 patients (16.3%). Among the outpatients with DVT, recurrent VTE occurred in 18 (3.0%) given edoxaban and in 21 (3.6%) given warfarin (risk difference: −0.61, 95% confidence interval [CI]: −2.6 to 1.4). The principal safety outcome in outpatients occurred in 46 edoxaban patients (7.7%) and in 48 warfarin patients (8.3%; risk difference: −0.59, 95% CI: −3.7 to 2.5). Most outpatients had symptomatic DVT at presentation. In these patients, initial heparin followed by edoxaban had similar efficacy and safety to standard therapy with heparin and warfarin.

Topics: Adult; Aged; Ambulatory Care; Anticoagulants; Double-Blind Method; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Pyridines; Thiazoles; United States; Venous Thromboembolism; 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

Better understanding of risk factors for major bleeding events during anticoagulant treatment for venous thromboembolism (VTE) may help physicians when deciding on intensity and duration of treatment. The primary aim of this study was to identify risk factors for major and clinically relevant bleeding in patients receiving the oral factor Xa inhibitor edoxaban or warfarin for the treatment of acute VTE. We analysed data from 8240 patients who received ≥1 dose of study drug in the Hokusai-VTE study. Bleeding risk factors were evaluated in 4118 patients who received edoxaban and significant variables were combined in a prediction model. We used the C-statistic to estimate model discrimination and bootstrap techniques for internal validation. Major bleeding occurred in 56/4118 (1.4 %) patients given edoxaban and in 66/4122 (1.6 %) patients given warfarin. Clinically relevant bleeding occurred in 349 (8.5 %) and 423 (10.3 %), respectively. Significant risk factors for major bleeding during edoxaban treatment were female sex, concomitant antiplatelet therapy, haemoglobin ≤10 g/dl, history of arterial hypertension, and systolic blood pressure >160 mmHg. The discrimination of the model was high (C-statistic: 0.71) for major bleeding, lower for clinically relevant bleeding (C-statistic: 0.62) and when the model was applied to patients receiving warfarin (C-statistic 0.60). In conclusion, we identified five main predictors of major bleeding in patients receiving edoxaban for the treatment of acute VTE. A risk model based on these factors predicted an increased risk of bleeding with good discrimination.

Topics: Aged; Anticoagulants; Blood Coagulation; Decision Support Techniques; Double-Blind Method; Factor Xa Inhibitors; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Predictive Value of Tests; Pyridines; Risk Assessment; Risk Factors; Thiazoles; Treatment Outcome; Venous Thromboembolism; Vitamin K; 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

One of the main determinants of establishing the optimal treatment duration of patients with venous thromboembolism (VTE) is the risk of major bleeding during long-term anticoagulant therapy. The 6-variable VTE-BLEED score was recently developed to enable estimation of this bleeding risk. This study aimed at externally validating VTE-BLEED. This was a post-hoc study of the randomised, double-blind, double-dummy, Hokusai-VTE study that compared edoxaban versus warfarin for treatment of VTE. VTE-BLEED was calculated in all 8,240 study patients. The numbers of adjudicated major bleeding events during 'stable anticoagulation', i. e. occurring after day 30, in patients with low (total score <2 points) and high risk of bleeding (total score ≥2 points) were compared for the overall study population, patients randomised to edoxaban or warfarin, and for important patient subcategories. During 'stable' anticoagulation, major bleeding occurred in 1.02 % (40/3,903) and 0.82 % (32/3,899) of patients treated with warfarin and edoxaban, respectively. For the overall study population, the risks of bleeding in the low and high risk groups were 0.51 % and 2.03 %, respectively, for an odds ratio (OR) of 4.04 (95 % confidence interval [CI]: 2.51-6.48). ORs were 5.04 (95 %CI: 2.62-9.69) and 3.09 (95 %CI: 1.54-6.22) for warfarin and edoxaban, respectively. VTE-BLEED was consistently able to identify patients at a 2.5- to 11-fold higher bleeding risk across all the predefined subcategories, as well as for the treatment period between day 30 to day 180, and beyond day 180. In conclusion, patients identified as high risk by VTE-BLEED had a four-fold increased risk of bleeding during the chronic phase of treatment.

Topics: Aged; Anticoagulants; Disease Progression; Female; Hemorrhage; Humans; Male; Middle Aged; Odds Ratio; Predictive Value of Tests; Prognosis; Pyridines; Research Design; Risk; Surveys and Questionnaires; Thiazoles; Venous Thromboembolism; 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

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

Edoxaban is a once-daily direct oral anticoagulant (DOAC). The Hokusai-VTE study revealed that, after initial treatment with heparin, edoxaban was non-inferior to and safer than vitamin K antagonists (VKA) in the prevention of recurrent deep-vein thrombosis and pulmonary embolism. This is the first report on the clinical relevance and management of bleeding events with edoxaban. All major bleeding events were classified blindly by three study-independent adjudicators. Pre-defined criteria were used to classify severity of clinical presentation and, separately, the clinical course and outcome into four categories. Major bleeding occurred in 56 patients treated with edoxaban and 65 patients treated with VKA. The severest categories (3 or 4) of the clinical presentation were assigned to 46 % of the major bleeding episodes in edoxaban recipients versus 58 % of the major bleeds in VKA recipients (odds ratio [OR] 0.62, 95 % confidence interval [CI] 0.30-1.27, p = 0.19). Clinical course was classified as severe (category 3 or 4) in 23 % of the edoxaban and 29 % of the VKA associated bleeds (OR 0.73, 95 % CI 0.32-1.66, p = 0.46). In conclusion, edoxaban associated major bleeding events have a comparable clinical presentation and course to major bleeds with VKA in patients treated for venous thromboembolism in the Hokusai-VTE study. These results may assure physicians that it is safe to prescribe this medication. If a major bleeding during edoxaban treatment occurs, its clinical presentation and clinical course are not worse than in VKA-treated patients.

Topics: Administration, Oral; Anticoagulants; Double-Blind Method; Factor Xa Inhibitors; Hemorrhage; Humans; Pyridines; Risk Factors; Thiazoles; Venous Thromboembolism; Vitamin K; 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

There are few data on the relative efficacy and safety of direct oral anticoagulants, such as edoxaban, compared with vitamin K antagonists during extended therapy for venous thromboembolism. This analysis evaluates the risk-benefit of extended treatment for up to 12 months with edoxaban compared with warfarin among patients enrolled in the Hokusai-VTE study who continued therapy beyond 3 months.. The Hokusai-VTE trial (NCT00986154) was a randomised, double-blind, event driven non-inferiority trial in 8292 patients comparing edoxaban with warfarin in the treatment of patients with acute venous thromboembolism. All patients were treated for at least 3 months and treatment was continued for up to 12 months. The outcomes at 12 months were documented in all patients irrespective of treatment duration. 3633 patients treated with edoxaban and 3594 treated with warfarin who completed 3 months of treatment were eligible for this analysis. The primary efficacy outcome was the incidence of adjudicated symptomatic recurrent venous thromboembolism evaluated for each of the time intervals of 3 months, greater than 3 months to 6 months, greater than 6 months to less than 12 months, and at 12 months, as well as the cumulative incidence occurring between 3 and 12 months. The principal safety outcome was the incidence of clinically relevant bleeding (composite of major or clinically relevant non-major bleeding). Both on-treatment and intention-to-treat analyses were done.. In the on-treatment analysis, the incidence of recurrent venous thromboembolism at 3 months was 1·1% (0·8-1·4; 44 of 4118 patients) in the edoxaban-treated group versus 1·2% (0·9-1·6; 51 of 4122) in the warfarin-treated group; between greater than 3 months and 6 months, 0·7% (0·3-1·5; eight of 1076) versus 0·5% (0·2-1·1; five of 1084); between greater than 6 months and less than 12 months, 0·2% (0·0-0·8; two of 896) versus 0·8% (0·03-1·7; seven of 851); and at 12 months, <0·1% (0·0-0·3; one of 1661) versus 0·1% (0·0-0·4; two of 1659). In the on-treatment analysis, the cumulative incidence of recurrent venous thromboembolism between 3 and 12 months was 0·3% (95% CI 0·2-1·5; 11 of 3633 patients) in the edoxaban-treated group and 0·4% (0·2-1·7; 14 of 3594) in the warfarin-treated group (HR 0·78, 95% CI 0·36-1·72). The cumulative incidence of clinically relevant bleeding (major or non-major) between 3 and 12 months was 3·9% (95% CI 3·3-4·6; 143 of 3633 patients) in the edoxaban-treated group and 4·1% (3·5-4·8; 147 of 3594 patients) in the warfarin-treated group (HR 0·97, 95% CI 0·77-1·22); cumulative incidence of major bleeding was 0·3% (95% CI 0·2-0·5; 11 of 3633 patients) in the edoxaban-treated group and 0·7% (0·4-1·0; 24 of 3594 patients) in the warfarin-treated group (HR 0·45, 95% CI 0·22-0·92). Similar results were obtained in the intention-to-treat analysis.. Extended treatment with edoxaban is effective and associated with less major bleeding than warfarin. Edoxaban once daily provides an attractive alternative to warfarin for patients with venous thromboembolism who require extended treatment for prevention of recurrent venous thromboembolism.. Daiichi Sankyo.

Topics: Adult; Aged; Anticoagulants; Comparative Effectiveness Research; Double-Blind Method; Female; Follow-Up Studies; Hemorrhage; Heparin; Humans; Male; Middle Aged; Pulmonary Embolism; Pyridines; Recurrence; Risk Assessment; Secondary Prevention; Thiazoles; Venous Thromboembolism; Ventricular Dysfunction, Right; 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

Edoxaban, an oral factor Xa inhibitor with 50% renal clearance, was noninferior to well-managed warfarin for stroke or systemic embolism (S/SE) prevention and reduced bleeding in patients with atrial fibrillation. We evaluated the efficacy and safety of edoxaban versus warfarin across the range of baseline creatinine clearance (CrCl) in the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction Study 48) with a focus on the higher-dose edoxaban regimen (HDER) and the upper range of CrCl.. A total of 14 071 patients with atrial fibrillation at moderate to high risk for stroke were randomized to warfarin or HDER (60 mg daily or a 50% dose reduction to 30 mg daily for CrCl 30-50 mL/min, body weight of ≤60 kg, or use of a potent phosphorylated glycoprotein inhibitor). CrCl <30 mL/min was exclusionary. End points of S/SE, International Society on Thrombosis and Haemostasis major bleeding, and the net clinical outcome of S/SE/major bleeding or death were evaluated by intention-to-treat analysis using the prespecified CrCl cut point of 50 mL/min and additional exploratory cut points with the Cockcroft-Gault formula. A sensitivity analysis was performed with the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula for estimating renal function.. The relative risk of S/SE with HDER versus warfarin in patients with CrCl >50 mL/min (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.72-1.04) was similar to that in patients with CrCl ≤50 mL/min (HR, 0.87; 95% CI, 0.65-1.18; P for interaction=0.94). Several exploratory analyses suggested lower relative efficacy for the prevention of S/SE with HDER compared with warfarin at higher levels of CrCl (CrCl ≤50 mL/min: HR, 0.87; 95% CI, 0.65-1.18; CrCl >50-95 mL/min: HR, 0.78; 95% CI, 0.64-0.96; CrCl >95 mL/min: HR, 1.36; 95% CI, 0.88-2.10; P for interaction=0.08). Bleeding rates were lower at all levels of CrCl with HDER (P for interaction=0.11). Because of the preserved effect on bleeding, the net clinical outcome was more favorable with HDER across the range of CrCl (P for interaction=0.73). Similar findings were observed in the sensitivity analysis using the CKD-EPI formula.. Although there was an apparent decrease in relative efficacy to prevent arterial thromboembolism in the upper range of CrCl, the safety and net clinical benefit of HDER compared with warfarin are consistent across the range of renal function.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Creatinine; Double-Blind Method; Factor Xa Inhibitors; Female; Follow-Up Studies; Hemorrhage; Humans; Kidney; Kidney Function Tests; Male; Metabolic Clearance Rate; Middle Aged; Pyridines; Risk; Thiazoles; Thrombophilia; 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

The oral factor Xa inhibitor edoxaban has demonstrated safety and efficacy in stroke prevention in patients with atrial fibrillation and in the treatment and secondary prevention of venous thromboembolism. This study investigated the reversal of edoxaban's effects on bleeding measures and biomarkers by using a 4-factor prothrombin complex concentrate (4F-PCC).. This was a phase 1 study conducted at a single site. This was a double-blind, randomized, placebo-controlled, 2-way crossover study to determine the reversal effect of descending doses of 4F-PCC on bleeding duration and bleeding volume following edoxaban treatment. A total of 110 subjects (17 in part 1, 93 in part 2) were treated. Intravenous administration of 4F-PCC 50, 25, or 10 IU/kg following administration of edoxaban (60 mg) dose-dependently reversed edoxaban's effects on bleeding duration and endogenous thrombin potential, with complete reversal at 50 IU/kg. Effects on prothrombin time were partially reversed at 50 IU/kg. A similar trend was seen for bleeding volume.. The 4F-PCC dose-dependently reversed the effects of edoxaban (60 mg), with complete reversal of bleeding duration and endogenous thrombin potential and partial reversal of prothrombin time following 50 IU/kg. Edoxaban alone and in combination with 4F-PCC was safe and well tolerated in these healthy subjects. A dose of 50 IU/kg 4F-PCC may be suitable for reversing edoxaban anticoagulation.. http://www.clinicaltrials.gov. Unique identifier: NCT02047565.

Topics: Administration, Intravenous; Adolescent; Adult; Biopsy, Needle; Blood Coagulation; Blood Coagulation Factors; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Prothrombin Time; Pyridines; Thiazoles; Time Factors; Young Adult

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

Compared with the coronary setting, knowledge about antithrombotic therapies after endovascular treatment (EVT) is inadequate in patients with peripheral artery disease (PAD). Based on a review of trials and guidelines, which is summarized in this article, there is scant evidence that antithrombotic drugs improve outcome after peripheral EVT. To address this knowledge gap, the randomized, open-label, multinational edoxaban in patients with Peripheral Artery Disease (ePAD) study (ClinicalTrials.gov identifier NCT01802775) was designed to explore the safety and efficacy of a combined regimen of antiplatelet therapy with clopidogrel and anticoagulation with edoxaban, a selective and direct factor Xa inhibitor, both combined with aspirin. As of July 2014, 203 patients (144 men; mean age 67 years) from 7 countries have been enrolled. These patients have been allocated to once-daily edoxaban [60 mg for 3 months (or 30 mg in the presence of factors associated with increased exposure)] or clopidogrel (75 mg/d for 3 months). All patients received aspirin (100 mg/d) for the 6-month duration of the study. The primary safety endpoint is major or clinically relevant nonmajor bleeding; the primary efficacy endpoint is restenosis or reocclusion at the treated segment(s) measured at 1, 3, and 6 months using duplex ultrasound scanning. All outcomes will be assessed and adjudicated centrally in a masked fashion. The ePAD study is the first of its kind to investigate a combined regimen of antiplatelet therapy and anticoagulation through factor Xa inhibition with edoxaban.

Topics: Aged; Angioplasty; Aspirin; Clopidogrel; Drug Therapy, Combination; Europe; Factor Xa Inhibitors; Female; Femoral Artery; Fibrinolytic Agents; Hemorrhage; Humans; Israel; Male; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Popliteal Artery; Pyridines; Research Design; Risk Factors; Stents; Thiazoles; Ticlopidine; Time Factors; Treatment Outcome; United States

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

Direct oral anticoagulants have been evaluated for their efficacy and safety in the treatment of venous thromboembolism (VTE), which comprises deep vein thrombosis and pulmonary embolism. The randomized, double-blind Hokusai-VTE trial demonstrated that 60 mg of edoxaban once daily following initial heparin treatment is non-inferior to heparin overlapped with and followed by warfarin for the treatment of VTE, and is associated with significantly fewer bleeding events.. To assess the efficacy and safety of edoxaban versus warfarin among East Asian patients enrolled in the Hokusai-VTE trial.. The Hokusai-VTE trial enrolled 8292 patients from 439 centers worldwide, including 1109 patients from Japan, China, Korea, and Taiwan. The primary efficacy and safety outcomes were symptomatic recurrent VTE and clinically relevant bleeding, respectively.. In the overall East Asian population, the primary efficacy outcome of symptomatic recurrent VTE occurred in 16 of 563 (2.8%) patients in the edoxaban group versus 24 of 538 (4.5%) patients in the warfarin group (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.34-1.19; P = 0.1601). The primary safety outcome of clinically relevant bleeding occurred in 56 of 563 (9.9%) patients in the edoxaban group versus 93 of 538 (17.3%) patients in the warfarin group (HR 0.56; 95% CI 0.40-0.78; P < 0.001).. Edoxaban is an effective and safer alternative to warfarin in East Asian patients with acute VTE who require anticoagulant therapy, consistent with overall study findings from the Hokusai-VTE trial.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Asia, Eastern; Asian People; Double-Blind Method; Factor Xa Inhibitors; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Pulmonary Embolism; Pyridines; Recurrence; Therapeutic Equivalency; Thiazoles; Venous Thromboembolism; Venous Thrombosis; Vitamin K; Warfarin; Young Adult

Direct oral anticoagulants may be effective and safe for treatment of venous thromboembolism (VTE) in cancer patients, but they have not been compared with low-molecular-weight heparin (LMWH), the current recommended treatment for these patients. The Hokusai VTE-cancer study is a randomised, open-label, clinical trial to evaluate whether edoxaban, an oral factor Xa inhibitor, is non-inferior to LMWH for treatment of VTE in patients with cancer. We present the rationale and some design features of the study. One such feature is the composite primary outcome of recurrent VTE and major bleeding during a 12-month study period. These two complications occur frequently in cancer patients receiving anticoagulant treatment and have a significant impact. The evaluation beyond six months will fill the current gap in the evidence base for the long-term treatment of these patients. Based on the observation that the risk of recurrent VTE in patients with active cancer is similar to that in those with a history of cancer, the Hokusai VTE-cancer study will enrol patients if whose cancer was diagnosed within the past two years. In addition, patients with incidental VTE are eligible because their risk of recurrent VTE is similar to that in patients with symptomatic disease. The unique design features of the Hokusai VTE-cancer study should lead to enrolment of a broad spectrum of cancer patients with VTE who could benefit from oral anticoagulant treatment.

Topics: Adult; Anticoagulants; Dalteparin; Double-Blind Method; Factor Xa Inhibitors; Hemorrhage; Humans; Neoplasms; Prospective Studies; Pulmonary Embolism; Pyridines; Recurrence; Research Design; Sample Size; Thiazoles; Time Factors; Treatment Outcome; Venous Thrombosis

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

Edoxaban is an oral, once-daily, direct factor Xa (FXa) inhibitor that has been evaluated for the prevention of stroke in patients with atrial fibrillation (AF) and for the treatment and prevention of venous thromboembolism (VTE) recurrence. Pharmacokinetic (PK) and pharmacodynamic (PD) modeling and logistic regression analyses were used to explore the clinical data from phase 1 and 2 studies to determine the relationship among PK exposure, PD response, and bleeding risk. Population PK/PD modeling was performed using plasma edoxaban concentration data from combined phase 1 and 2 studies and using intrinsic FXa data from a phase 2 AF study. A 2-compartment PK model adequately described the combined PK data, and a dynamic binding model characterized the dynamics of the intrinsic factor X activity (iFXa) data. Logistic regression analysis then identified the relationship between the iFXa and the observed bleeding risk. The more protracted suppression of FXa over the dosing interval for a 30-mg twice-daily dose compared with a 60-mg once-daily dose offers an explanation for the significantly higher bleeding rate at the former dose.

Topics: Adult; Aged; Factor Xa; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Models, Biological; Pyridines; Thiazoles

The aim of this study was to evaluate the population pharmacokinetics (PK) and exposure-response relationship of edoxaban in patients with non-valvular atrial fibrillation (AF).. Concentration data from 1,134 subjects in 11 clinical studies (eight phase I, one phase II, and two phase III) were used to perform a population PK analysis, including estimation of the bioavailability and quantification of the effects of P-glycoprotein (P-gp) inhibitors as well as renal impairment on edoxaban PK. The potential relationship between edoxaban PK exposure and incidence of bleeding events was explored based on data from 893 AF patients.. Absolute bioavailability of edoxaban was estimated as 58.3 %. With oral dosing of edoxaban, co-administration of various P-gp inhibitors significantly increased edoxaban bioavailability and decreased volume of distribution (V 2), resulting in a predicted increase of 33-77 % in area under the curve (AUC) and 65-104 % in C max. A much smaller increase was seen in edoxaban concentration at 24 h post-dose (C 24, -24 to 38 %), due to decreased V 2 and shortened elimination half-life. With IV dosing of edoxaban, co-administration of the P-gp inhibitor quinidine decreased both edoxaban clearance (CL) and V 2, resulting in an increase of 32 % in AUC and 66 % in C 24. Creatinine clearance was a significant covariate on renal clearance, whereas age and body weight significantly affected nonrenal clearance. Model-predicted steady state C min was slightly higher, but AUC was comparable for patients who had severe renal impairment and received edoxaban 15 mg once daily (QD) versus patients who had normal renal function or mild renal impairment and received edoxaban 30 mg QD. Exposure-response analysis suggested that edoxaban C min and country/region are significantly associated with the incidence of bleeds.. The model provided reasonable estimation with regard to the absolute bioavailability of edoxaban, the magnitude of change in edoxaban exposure upon co-administration of P-gp inhibitors, and the impact of renal impairment on edoxaban clearance. Analysis results supported a 50 % dose reduction scheme for subjects with severe renal impairment. Further confirmation will be sought by incorporating clinical safety and efficacy information from larger phase III trials.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; ATP Binding Cassette Transporter, Subfamily B, Member 1; Atrial Fibrillation; Biological Availability; Dose-Response Relationship, Drug; Female; Hemorrhage; Humans; Male; Middle Aged; Models, Biological; Pyridines; Quinidine; Renal Insufficiency; Thiazoles; Young Adult

New oral anticoagulants may simplify long-term therapy by eliminating the need for laboratory monitoring. Edoxaban is an oral, direct inhibitor of factor Xa that is given in a fixed dose once daily.. The Hokusai-VTE study is a randomized, double-blind trial to evaluate whether initial low molecular weight heparin (LMWH) followed by edoxaban (60 mg once daily) is non-inferior to LMWH followed by warfarin (International Normalized Ratio of 2.0-3.0) for the prevention of recurrent thromboembolism in patients with acute symptomatic venous thromboembolism (VTE). The primary efficacy outcome is symptomatic recurrent VTE during the 12-month study period. The principal safety outcome is clinically relevant bleeding (major or non-major) occurring during or within 3 days of stopping study treatment. A clinical events committee adjudicates all suspected outcome events. A unique study design feature is the flexible treatment duration of between 3 and 12 months to simulate usual clinical practice, and enabled by: (i) double-blinding to minimize bias that could occur if knowledge of the patient's treatment influenced the duration of therapy; and (ii) follow-up for 12 months of all patients and inclusion in the primary efficacy analysis, regardless of the duration of therapy received. A second innovative design feature is the strategy for achieving an appropriate time in therapeutic range in the warfarin group, with central tracking for each participating center and feedback to the investigators.. The standard methods combined with innovative design features should achieve study results that are both scientifically valid and relevant to clinical practice.

Topics: Administration, Oral; Anticoagulants; Blood Coagulation; Blood Coagulation Tests; Clinical Protocols; Double-Blind Method; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Predictive Value of Tests; Pyridines; Research Design; Secondary Prevention; Thiazoles; Time Factors; Treatment Outcome; Venous Thromboembolism; 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

Currently venous thromboembolic disease (VTE), i.e. deep venous thrombosis and pulmonary embolism, remains a major cause of morbidity and mortality all around the world. The Hokusai-VTE study is a randomized, double-blind trial to evaluate whether initial heparin (5 days) followed by the oral Xa factor inhibitor edoxaban (60 mg once daily) may be an alternative to the standard therapy, i.e. heparin (5 days) followed by warfarin (INR of 2.0-3.0) for the prevention of recurrent thromboembolism in patients with acute symptomatic VTE. In patients with VTE, including pulmonary embolism with right ventricular dysfunction, treatment with heparin followed by oral edoxaban 60 mg once daily was non inferior to the standard treatment with respect to efficacy and superior with respect to bleeding (fewer fatal and intracranial bleeds, but no statistical significance regarding major bleeding). Reducing the dosage of edoxaban to 30 mg once daily is safe in case of renal impairment and low body weight.

Topics: Anticoagulants; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Hemorrhage; Heparin; Humans; Pyridines; Randomized Controlled Trials as Topic; Thiazoles; Venous Thromboembolism; 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

Factor Xa (FXa) is a key serine protease in the coagulation cascade and a promising target for a new antithrombotic agent. Edoxaban is an oral, selective and direct FXa inhibitor. The objective of this study was to compare the antithrombotic and haemorrhagic effects of edoxaban with clinically available anticoagulants, warfarin and enoxaparin, in rat models of thrombosis and haemorrhage.. Rats were treated with single oral administration of edoxaban, repeated oral dosing of warfarin for 4 days and single subcutaneous administration of enoxaparin before thrombosis or haemorrhage induction. Thrombosis was induced by the insertion of a platinum wire into the inferior vena cava for 60 min. Tail template bleeding time was measured after making an incision on the tail.. Edoxaban at 0.3, 1 and 3mg/kg exerted dose-dependent and significant inhibition of venous thrombus formation. The 50% thrombus inhibition dose (ED(50)) was 1.9 mg/kg. At supra-therapeutic doses (10 and 20mg/kg), edoxaban significantly but moderately (less than 2-fold) prolonged bleeding time. Warfarin and enoxaparin also dose-dependently inhibited venous thrombosis and prolonged bleeding time. The ED(50) values of warfarin and enoxaparin were 0.12 mg/kg and 500 IU/kg, and the 2-fold bleeding time prolongation doses (BT2) were 0.16 mg/kg and 1700 IU/kg, respectively. The safety margin (ratio of BT2 to ED(50)) of edoxaban (>10.5) was greater than those of warfarin (1.3) and enoxaparin (3.4).. Edoxaban inhibited venous thrombosis comparably to warfarin and enoxaparin, and the attendant bleeding risk of edoxaban was lower than that of warfarin and enoxaparin in rats.

Topics: Administration, Oral; Animals; Anticoagulants; Enoxaparin; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Hemostatics; Male; Pyridines; Rats; Rats, Wistar; Thiazoles; Treatment Outcome; Venous Thrombosis; Warfarin

Edoxaban is a once-daily (QD) oral, direct factor Xa inhibitor in clinical development for the prevention of stroke in patients with non-valvular atrial fibrillation (NVAF). The aim of this study was to evaluate the safety of edoxaban in Japanese patients with NVAF.. A total of 536 NVAF patients (CHADS2 ≥1) were randomized to receive double-blinded edoxaban 30, 45, or 60 mg QD or open-label warfarin (international normalized ratio [INR] 2.0-3.0 for age <70 years; 1.6-2.6 for age ≥70 years) for 12 weeks. The primary endpoint was the incidence of all bleeding events (major, clinically relevant non-major, and minor bleeds). Patients underwent CT and/or MRI to assess asymptomatic intracranial hemorrhage (ICH). Secondary endpoints included thromboembolic events and pharmacodynamic indices. The mean incidence of all bleeding events for edoxaban 30, 45, and 60mg, and warfarin was 18.5%, 22.4%, 27.7%, and 20.0%, respectively. There were no statistically significant differences among the edoxaban groups and no significant differences from the warfarin group. There were no asymptomatic ICH events in any group. One episode of cerebral infarction was observed in the edoxaban 45-mg group. Subgroup analysis suggested low body weight (≤60kg) was associated with higher bleeding risk.. Edoxaban 30, 45, and 60mg QD in patients with NVAF was associated with a numerical increase in all bleeding across the dose range, but this was not statistically significant, nor was any dose compared with warfarin.

Topics: Aged; Anticoagulants; Asian People; Atrial Fibrillation; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hemorrhage; Humans; Incidence; International Normalized Ratio; Japan; Male; Middle Aged; Pyridines; Thiazoles; Warfarin

Edoxaban is an oral, reversible, direct factor Xa inhibitor in phase III clinical development for the prevention of stroke in atrial fibrillation (AF). A phase II study was undertaken to evaluate the safety and efficacy of edoxaban in Asian patients with non-valvular AF with CHADS2 score ≥1. In a multicentre, active-controlled, double-blind edoxaban and open-label warfarin, parallel-group study, a total of 235 patients from four Asian countries were randomly assigned to edoxaban 30 mg qd, 60 mg qd or warfarin dose adjusted to international normalised ratio of 2-3 for three months. The primary endpoint was the incidence of centrally adjudicated all bleeding events (major, clinically relevant non-major and minor). Secondary endpoints included thromboembolic events, biomarkers of thrombus formation and all adverse events (AEs). The incidence of all bleeding events (95% CI) was 20.3% (12.9, 30.4) for edoxaban 30 mg, 23.8% (15.8, 34.1) for edoxaban 60 mg, and 29.3% (20.2, 40.4) for warfarin. A subgroup analysis suggested low body weight (≤60 kg) may affect the incidence of bleeding events with edoxaban. The incidence of study drug-related AEs was 22% for edoxaban 30 mg, 29% for edoxaban 60 mg and 33% for warfarin. No thromboembolic events occurred in any treatment group. In conclusion, this phase II study found a trend for a reduction in the incidence of all bleeding events in Asian AF patients with edoxaban 30 mg and 60 mg compared with warfarin. Adverse events were similar between the edoxaban 60-mg and warfarin groups and were lower with the edoxaban 30-mg group.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Asian People; Atrial Fibrillation; Double-Blind Method; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Middle Aged; Pyridines; Thiazoles; Warfarin

Edoxaban is a new oral direct factor Xa inhibitor. The purpose of this study was to evaluate the efficacy and safety of different doses of edoxaban for the prevention of venous thromboembolism (VTE) in patients undergoing elective total hip replacement. A total of 903 patients were randomised to oral edoxaban 15, 30, 60 or 90 mg once daily or subcutaneous dalteparin once daily (initial dose 2,500 IU, subsequent doses 5,000 IU). Both drugs were begun 6-8 hours postoperatively and continued for 7-10 days, when bilateral venography was performed. The primary efficacy endpoint was the incidence of total VTE, which included proximal and/or distal deep-vein thrombosis (DVT) by venography or symptomatic, objectively confirmed DVT or pulmonary embolism during the treatment period. The primary safety outcome was the incidence of the composite of major and clinically relevant non-major bleeding. All venograms and bleeding events were reviewed by a central independent adjudication committee blinded as to treatment allocation. Of the 903 patients randomised, 776 were evaluable for the primary efficacy analysis. The incidences of VTE were 28.2%, 21.2%, 15.2%, and 10.6% in patients receiving edoxaban 15, 30, 60 and 90 mg, respectively, compared with 43.8% in the dalteparin group (p<0.005 ). There was a statistically significant (p<0.001) dose-response for efficacy across the edoxaban dose groups for total VTE and for major VTE. The incidence of clinically relevant bleeding was low and similar across the groups. Oral edoxaban once daily is effective for preventing VTE after total hip replacement.

Topics: Administration, Oral; Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Canada; Dalteparin; Double-Blind Method; Drug Administration Schedule; Elective Surgical Procedures; Europe; Factor Xa; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Hemorrhage; Humans; Injections, Subcutaneous; Logistic Models; Male; Middle Aged; Phlebography; Pulmonary Embolism; Pyridines; Risk Assessment; Risk Factors; Thiazoles; Time Factors; Treatment Outcome; United States; Venous Thromboembolism; Venous Thrombosis

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

Edoxaban (the free base of DU-176b) is an oral, direct factor (F)Xa inhibitor in clinical development for the prevention and treatment of thromboembolic events.. The aim of the present study was to evaluate the efficacy and safety of edoxaban for the prevention of venous thromboembolism (VTE) in patients undergoing total knee arthroplasty (TKA).. This was a randomized, double-blind, placebo-controlled, multicenter study conducted in Japan. A total of 523 Japanese patients were assigned to receive edoxaban 5, 15, 30 or 60 mg once daily or placebo for 11-14 days. A placebo control was used as neither low-molecular-weight heparin (LMWH) nor fondaparinux had been approved for thromboprophylaxis at the time of the study in Japan. The primary efficacy outcome was the incidence of VTE (lower-extremity deep vein thrombosis, symptomatic pulmonary embolism or symptomatic deep vein thrombosis). The primary safety outcome was the incidence of major and clinically relevant non-major bleeding.. Edoxaban produced a significant dose-related reduction in VTE: the incidence of VTE was 29.5%, 26.1%, 12.5% and 9.1% in the edoxaban 5-, 15-, 30- and 60-mg treatment groups vs. 48.3% in the placebo group. The incidence of major and clinically relevant non-major bleeding was similar across all groups without any significant differences among edoxaban doses or between edoxaban and placebo.. Edoxaban demonstrated significant dose-dependent reductions in VTE in patients undergoing TKA with a bleeding incidence similar to placebo. [This trial is registered with JAPIC, JapicCTI-060283 (ja).].

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Arthroplasty, Replacement, Knee; Dose-Response Relationship, Drug; Double-Blind Method; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Japan; Middle Aged; Placebos; Pyridines; Thiazoles; Venous Thromboembolism

Extensive data support the superior safety without any trade-off in efficacy of direct oral anticoagulants (DOACs) compared to vitamin K antagonists (VKA) in patients with nonvalvular atrial fibrillation, deep venous thrombosis or pulmonary embolism. Whether DOACs may be successfully used to treat complex and fragile patients with percutaneous endoscopic gastrostomy (PEG) remains to be proven. The purpose of this pilot study was to evaluate the feasibility, anticoagulant effect, and preliminary safety/efficacy profile of edoxaban administered via PEG in patients with an indication for long-term oral anticoagulation.. In this prospective, single-arm, pilot study, 12 patients with PEG and guideline-recommended indication for anticoagulation for nonvalvular atrial fibrillation were prospectively enrolled. Crushed edoxaban at approved doses was administered via PEG. Quantitative measures of edoxaban's antifactor Xa activity were performed at steady state. Thromboembolic and bleeding events were assessed at one-month follow-up.. Steady state edoxaban plasma levels were at therapeutic range in all patients; mean plasma concentration was 208.5 (±78.6) ng/mL. At one month follow-up, none had suffered a thromboembolic event; one developed minor bleeding, and one died from non-cardiovascular death, owing to sudden worsening of a pre-existing underlying severe condition.. In this pilot investigation, we report for the first time that crushed edoxaban, administered at approved doses through PEG in fragile and complex patients, is feasible, results in therapeutic edoxaban concentrations, and is apparently effective and safe.

Topics: Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Gastrostomy; Hemorrhage; Humans; Pilot Projects; Prospective Studies; Thromboembolism

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

Over the past 20 years, there has been a shift from vitamin K antagonists to direct oral anticoagulants (DOACs), which include the thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban, edoxaban, and rivaroxaban. Although DOACs are associated with less serious bleeding than vitamin K antagonists, bleeding still occurs with DOACs, particularly in the elderly and in those with comorbidities. Reversal of the anticoagulant effects of the DOACs may be needed in patients with serious bleeding and in those requiring urgent surgery or intervention. Reversal can be effected with specific agents, such as idarucizumab for dabigatran and andexanet alfa for apixaban, edoxaban, and rivaroxaban, or with non-specific agents, such as prothrombin complex concentrates, activated prothrombin complex concentrate, and recombinant activated factor VII. This paper (i) provides an update on when and how to reverse the DOACs, (ii) describes new reversal agents under development, and (iii) provides a strategic framework for the reversal of the factor XI inhibitors currently under investigation in phase three clinical trials.

Topics: Administration, Oral; Aged; Anticoagulants; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Recombinant Proteins; Rivaroxaban; Vitamin K

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

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

Edoxaban is given as pharmacologic prophylaxis alone or in combination with mechanical prophylaxis for venous thromboembolism after total knee arthroplasty. Several choices are made regarding edoxaban dosages when used in combination with mechanical prophylaxis. This study aimed to compare efficacy and safety in patients who received edoxaban with elastic stockings after total knee arthroplasty between those who received the standard dose, including those who received a reduced dose after meeting dose reduction criteria, and those who received reduced doses without dose reduction criteria.. This study included 143 patients in the standard-dose group (with 125 patients receiving dose-adjusted edoxaban 15 mg/day) and 110 patients in the low-dose group, and it compared the incidence of venous thromboembolism and bleeding events between groups. The impact of edoxaban administration on the occurrence of venous thromboembolism after total knee arthroplasty was also examined using multivariate regression analysis.. Our results showed that rates of venous thromboembolism and bleeding events in patients wearing elastic stockings after total knee arthroplasty were similar in both standard- and low-dose groups. Multivariate regression analysis showed that use of reduced-dose edoxaban without dose adjustment did not correlate with the occurrence of venous thromboembolism, but edoxaban administration was significantly associated with older age and longer surgery time (odds ratio 1.84, 95% confidence interval 1.04 - 3.25, p = 0.036; odds ratio 1.69; 95% confidence interval 1.09 - 2.62, p = 0.019).. These results suggest that reduced dose selection of edoxaban for patients who receive mechanical prophylaxis after total knee arthroplasty and post-administration pharmacological management may be useful.

Topics: Anticoagulants; Arthroplasty, Replacement, Knee; Hemorrhage; Humans; Pyridines; Retrospective Studies; Venous Thromboembolism

Limited data were published on the management of direct oral anticoagulants in the insertion of pacemaker and cardiac monitoring devices. This study describes the management and outcomes of edoxaban, a direct oral factor Xa inhibitor, in patients undergoing pacemaker or monitoring device implantation in routine clinical practice.. EMIT-AF/VTE collected data of patients from Europe, Korea, and Taiwan. Timing and duration of periprocedural interruption of edoxaban were at the treating physician's discretion. Pacemakers or monitoring devices were implanted into 136 patients who were evaluated from 5 days pre- until 30 days post-procedure. The primary outcomes were the incidences of acute thromboembolic events (ATE), ischemic events, and International Society on Thrombosis and Haemostasis-defined Major Bleeding; secondary outcomes included incidence of clinically relevant non-major bleeding (CRNMB) and perioperative edoxaban interruption times. Conformance with European Heart Rhythm Association (EHRA) Guidance on interruption of direct oral anticoagulant therapy was variable: of the cardiac monitoring device patients, where no interruption of therapy would be expected, nonetheless, 62.5% had interruption of treatment, whereas in pacemaker procedures, where interruption would be expected, 23.4% had no interruption. No ATE or ischemic events occurred. One case of CRNMB and two of minor bleeding occurred. All bleedings occurred more than 3 days after the procedure.. The periprocedural complication risk for edoxaban treated patients undergoing pacemaker or invasive cardiac monitoring implantation was low. This population of patients was well managed in routine practice.

Topics: Aged; Anticoagulants; Cardiac Resynchronization Therapy Devices; Europe; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Ischemia; Male; Pacemaker, Artificial; Prospective Studies; Pyridines; Republic of Korea; Risk Factors; Taiwan; Thiazoles; Thromboembolism

 Andexanet alfa (andexanet) is approved for specific anticoagulation reversal in patients with life-threatening or uncontrolled bleeding during treatment with rivaroxaban or apixaban. There is limited experience with andexanet in patients with acute bleeding on edoxaban..  Patients with acute major bleeding within 18 hours of edoxaban intake were prospectively enrolled. Patients received a bolus and 2-hour follow-on infusion of andexanet. The co-primary efficacy outcomes were change in antifactor Xa activity and the percentage of patients achieving excellent or good hemostasis, 12 hours after andexanet treatment. Efficacy was analyzed in patients with confirmed major bleeding and baseline antifactor Xa activity ≥40 ng/mL. Safety was analyzed in all patients..  In patients with acute major bleeding on edoxaban, andexanet significantly decreased antifactor Xa activity. Hemostatic efficacy was similar to that observed in patients with bleeding on rivaroxaban or apixaban. Thrombotic events occurred at a rate expected in such patients.

Topics: Aged, 80 and over; Anticoagulation Reversal; Factor Xa; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Pyridines; Recombinant Proteins; Thiazoles; Thrombosis

Van Mieghem NM, Unverdorben M, Hengstenberg C, et al.

Topics: Anticoagulants; Atrial Fibrillation; Hemorrhage; Humans; Pyridines; Thiazoles; Transcatheter Aortic Valve Replacement

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

Although initial therapy with a parenteral anticoagulant is required before edoxaban, this strategy is frequently avoided in actual clinical practice because of its complexity. This study assessed the feasibility of edoxaban without initial heparin usage for asymptomatic cancer-associated thrombosis (CAT) in Japanese patients with gastrointestinal cancer (GIC) at high risk of bleeding.. In this multicenter prospective feasibility study conducted at 10 Japanese institutions, patients with active GIC who developed accidental asymptomatic CAT during chemotherapy were recruited. Edoxaban was orally administered once daily without initial parenteral anticoagulant therapy within 3 days after detecting asymptomatic CAT. The primary outcome was the incidence of major bleeding (MB) or clinically relevant non-major bleeding (CRNMB) during the first 3 months of edoxaban administration.. Of the 54 patients enrolled from October 2017 to September 2020, one was excluded because of a misdiagnosis of CAT. In the remaining 53 patients, the primary outcome occurred in six patients (11.3%). MB occurred in four patients (7.5%), including gastrointestinal bleeding in three patients and intracranial hemorrhage in one patient. CRNMB occurred in two patients (3.8%), including bleeding from the stoma site and genital bleeding in one patient each. There were no deaths attributable to bleeding, and all patients who experienced MB or CRNMB recovered.. The risk of bleeding after edoxaban without heparin pretreatment was acceptable, demonstrating new treatment options for asymptomatic CAT in patients with GIC.

Topics: Anticoagulants; East Asian People; Factor Xa Inhibitors; Feasibility Studies; Gastrointestinal Neoplasms; Hemorrhage; Heparin; Humans; Prospective Studies; Thrombosis

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

The effects of catheter ablation (CA) energy sources on myocardial injury and coagulation biomarkers among Japanese non-valvular atrial fibrillation patients receiving uninterrupted periprocedural edoxaban are unclear. This KYU-RABLE exploratory subanalysis compared the effects of CA using radiofrequency energy vs. cryoballoon on: (1) myocardial injury; and (2) plasma edoxaban and coagulation biomarker concentrations measured before and after CA.Methods and Results:Plasma creatine kinase (CK), edoxaban, D-dimer, and prothrombin fragment 1+2 (F1+2) concentrations within 1 h before CA were compared with concentrations the day after. All biomarkers increased after CA, regardless of the energy source, but especially with cryoballoon. Significantly higher increases in CK concentrations from before to the day after CA were seen with cryoballoon compared with radiofrequency energy (P<0.0001). Edoxaban concentrations were similar in both groups. Concentrations of D-dimer and F1+2 increased in both groups, but were significantly higher in the cryoballoon group (P<0.0001 and P=0.006, respectively). There were no significant between-group differences in the incidence of thrombotic or bleeding events.. Uninterrupted edoxaban concentrations were similar in both groups. Both myocardial injury and coagulation biomarkers increased after CA, especially with cryoballoon, but there was no difference in the incidence of thrombotic or bleeding events. These findings suggest the efficacy of uninterrupted edoxaban, regardless of the CA energy source. Periprocedural anticoagulation, particularly with cryoballoon, should be undertaken with care.

Topics: Anticoagulants; Atrial Fibrillation; Biomarkers; Catheter Ablation; Heart Injuries; Hemorrhage; Humans; Pyridines; Thiazoles; Treatment Outcome

Direct oral anticoagulants (DOACs) are widely used for the prevention of ischemic stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). However, the differences in safety and effectiveness among four DOACs, dabigatran, rivaroxaban, apixaban, and edoxaban, in Japanese patients have not been clarified. Therefore, we conducted a retrospective cohort study to directly compare the safety and effectiveness among the four DOACs using the Japan Medical Data Center (JMDC) claims database. We identified 3823 patients with NVAF who started receiving a DOAC between March 2011 and June 2017. The safety outcome was major bleeding (a composite outcome of intracranial, gastrointestinal, respiratory, or renal/urinary tract bleeding) and the effectiveness outcome was the composite of ischemic stroke including transient ischemic attack (TIA) or systemic embolism. We constructed a Cox proportional hazard model to calculate the hazard ratio (HR) for all four DOAC combinations. The risk of major bleeding was significantly lower in the dabigatran group than in the apixaban group (HR, 0.55; 95% confidence interval (CI), 0.31-0.93; p = 0.03). In contrast, there was no significant difference in the risk of major bleeding among the other DOACs. In the composite risk of ischemic stroke including TIA or systemic embolism, there was no significant difference among the four DOACs. This study suggested that in the current use of DOACs in Japanese patients with NVAF, dabigatran had a significantly lower risk of major bleeding than apixaban, but there was no significant difference in effectiveness among the four DOACs.

Topics: Administration, Oral; Administrative Claims, Healthcare; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Hemorrhage; Humans; Ischemic Attack, Transient; Ischemic Stroke; Japan; Male; Middle Aged; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Rivaroxaban; Thiazoles

Several direct oral anticoagulants have been developed to prevent cardiogenic thrombosis in patients with atrial fibrillation, on the other hand, have the complication of bleeding. Since clinical course after bleeding with direct oral anticoagulant remains unclear, the present retrospective cohort study was to clarify the course after hemorrhage among patients receiving direct oral anticoagulants. Among all 2005 patients prescribed dabigatran, rivaroxaban, apixaban, or edoxaban between April 2011 and June 2017, subjects comprised 96 patients with non-valvular atrial fibrillation who experienced relevant bleeding during direct oral anticoagulant therapy (Bleeding Academic Research Consortium type 2 or above). The clinical course after hemorrhage was reviewed to examine whether rebleeding or thrombotic events occurred up to the end of December 2019. Gastrointestinal bleeding was the most frequent cause of initial bleeding (57 patients, 59%). Rebleeding occurred in 11 patients (4.5%/year), with gastrointestinal bleeding in 10 and subarachnoid hemorrhage in 1. All rebleeding occurred in patients who resumed anticoagulation therapy. Another significant factor related with rebleeding included past history of gastrointestinal bleeding. On the other hand, major adverse cardiac and cerebrovascular events occurred in 6 patients older than 75 years old or more (2.5%/year), with systemic thrombosis in 4 and cardiac death in 2. All 4 patients with systemic thrombosis withheld anticoagulants after index bleeding, although only 10 patients withheld anticoagulation therapy. Rebleeding should be taken care of when anticoagulants are resumed after bleeding, particularly among patients who initially experienced gastrointestinal bleeding. Systemic thrombosis occurred at a high rate when anticoagulant therapy was withheld after bleeding.

Topics: Aged; Aged, 80 and over; Atrial Fibrillation; Dabigatran; Factor Xa Inhibitors; Female; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Male; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Rivaroxaban; Thiazoles; Thrombosis

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

Edoxaban is used for venous thromboembolism (VTE) treatment. Real-life data are lacking about its use in long-term therapy. We aimed to assess the efficacy and the safety of edoxaban for long-term VTE treatment in a real-life setting. Patients with VTE included in the Registro Informatizado Enfermedad TromboEmbólica (RIETE) registry, receiving edoxaban 60 or 30 mg daily were prospectively followed up to validate the benefit of using different dosages. The main outcome was the composite of VTE recurrences or major bleeding in patients with or without criteria for dose reduction. Multivariable analysis to identify predictors for the composite outcome was performed. From October 2015 to November 2019, 562 patients received edoxaban for long-term therapy. Most (94%) of the 416 patients not meeting criteria for dose reduction received 60 mg daily, and 92 patients meeting criteria (63%) received 30 mg daily. During treatment, two patients developed recurrent VTE, six had major bleeding and nine died (2 from fatal bleeding). Among patients not meeting criteria for dose reduction, those receiving 30 mg daily had a higher rate of the composite event (hazard ratio (HR) 8.37; 95% confidence interval (CI) 1.12-42.4) and a significant higher mortality rate (HR 31.1; 95% CI 4.63-262) than those receiving 60 mg. Among patients meeting criteria for dose reduction, those receiving 60 mg daily had no events, and a nonsignificantly higher mortality rate (HR 5.04; 95% CI 0.54-133) than those receiving 30 mg daily. In conclusion, edoxaban seems to be effective and safe for long-term VTE treatment in real life. Criteria for dose reduction should be reformulated.

Topics: Aged; Aged, 80 and over; Anticoagulants; Dose-Response Relationship, Drug; Drug Tapering; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Practice Guidelines as Topic; Prospective Studies; Pyridines; Recurrence; Registries; Thiazoles; Time Factors; Venous Thromboembolism

Splanchnic vein thrombosis (SVT) is an uncommon but potentially life-threatening disease usually related to different underlying clinical conditions. The risk of SVT recurrences is high over time in patients with an underlying permanent prothrombotic condition. Vitamin K antagonists (VKA) represent the mainstay of treatment for SVT. Data about the efficacy and safety of direct oral anticoagulants (DOACs) are reported in the literature for the treatment of acute SVT, but less is known about their application for the secondary prophylaxis of venous thromboembolism (VTE). The aim of this study was to assess the efficacy and safety of long-term DOACs therapy in patients at high-risk of thrombosis, compared to VKA.. This is a retrospective single-centre study including 70 patients with SVT on long-term anticoagulant treatment with VKA followed-up at our Units between January 2017 and December 2019. All the patients were at high thrombotic risk defined as the presence of a permanent prothrombotic condition requiring long-term anticoagulation. During follow-up, 28 patients were shifted to DOACs and their clinical outcomes were compared to those of the patients who continued VKA therapy. All the arterial and venous thrombotic events of the splanchnic and extra-splanchnic districts as well as the haemorrhagic adverse events occurring during follow-up were recorded.. Of the seventy patients enrolled in the study, 36 patients (51.4%) had a single-segment involvement thrombosis (28.5% of portal vein, 7.1% of superior mesenteric vein, 4.3% of splenic vein, 11.5% of hepatic veins) and 34 patients (48.6%) had multi-segment involvement at the time of diagnosis. 42 patients (60%) continued VKA therapy and 28 (40%) were switched to DOACs. Median follow-up was 6 years (range 2-8) during VKA and 1.9 years (range 1-5.2) during DOACs. The incidence of thrombotic events was similar between patients on VKA and those on DOACs. Patients on VKA developed deep vein thrombosis (DVT), and of the patients on DOACs 1 developed NSTEMI and 1 DVT. No major haemorrhagic events occurred. Minor bleedings occurred in 26% of patients on VKA and in none of the DOACs patients (P: 0.09).. Our results highlight that DOACs could represent an effective and safe alternative to the VKA for secondary prophylaxis in SVT patients at high risk of thrombosis.

Topics: Acenocoumarol; Adult; Anticoagulants; Budd-Chiari Syndrome; Duration of Therapy; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Mesenteric Ischemia; Middle Aged; Portal Vein; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Secondary Prevention; Thiazoles; Venous Thrombosis; Warfarin

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

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

It is unclear how many patients treated with a direct oral anticoagulant (DOAC) are using concomitant acetylsalicylic acid (ASA, or aspirin) and how this affects clinical outcomes.. To evaluate the frequency and outcomes of prescription of concomitant ASA and DOAC therapy for patients with atrial fibrillation (AF) or venous thromboembolic disease (VTE).. This registry-based cohort study took place at 4 anticoagulation clinics in Michigan from January 2015 to December 2019. Eligible participants were adults undergoing treatment with a DOAC for AF or VTE, without a recent myocardial infarction (MI) or history of heart valve replacement, with at least 3 months of follow-up.. Use of ASA concomitant with DOAC therapy.. Rates of bleeding (any, nonmajor, major), rates of thrombosis (stroke, VTE, MI), emergency department visits, hospitalizations, and death.. Of the study cohort of 3280 patients (1673 [51.0%] men; mean [SD] age 68.2 [13.3] years), 1107 (33.8%) patients without a clear indication for ASA were being treated with DOACs and ASA. Two propensity score-matched cohorts, each with 1047 patients, were analyzed (DOAC plus ASA and DOAC only). Patients were followed up for a mean (SD) of 20.9 (19.0) months. Patients taking DOAC and ASA experienced more bleeding events compared with DOAC monotherapy (26.0 bleeds vs 31.6 bleeds per 100 patient years, P = .01). Specifically, patients undergoing combination therapy had significantly higher rates of nonmajor bleeding (26.1 bleeds vs 21.7 bleeds per 100 patient years, P = .02) compared with DOAC monotherapy. Major bleeding rates were similar between the 2 cohorts. Thrombotic event rates were also similar between the cohorts (2.5 events vs 2.3 events per 100 patient years for patients treated with DOAC and ASA compared with DOAC monotherapy, P = .80). Patients were more often hospitalized while undergoing combination therapy (9.1 vs 6.5 admissions per 100 patient years, P = .02).. Nearly one-third of patients with AF and/or VTE who were treated with a DOAC received ASA without a clear indication. Compared with DOAC monotherapy, concurrent DOAC and ASA use was associated with increased bleeding and hospitalizations but similar observed thrombosis rate. Future research should identify and deprescribe ASA for patients when the risk exceeds the anticipated benefit.

Topics: Anticoagulants; Aspirin; Atrial Fibrillation; Dabigatran; Drug Therapy, Combination; Female; Hemorrhage; Humans; Male; Pyrazoles; Pyridines; Pyridones; Registries; Rivaroxaban; Thiazoles; Venous Thromboembolism

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

Topics: Atrial Fibrillation; Biomarkers; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Proteomics; Pyridines; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Thiazoles; Thromboembolism

Edoxaban has three dose adjustment factors (creatinine clearance, 15-50 mL/min; body weight, 60 kg or less; and concomitant medication with potent P-glycoprotein inhibitors) to prevent bleeding that results from elevated blood concentrations of the drug. A dose reduction (from 60 to 30 mg/day of edoxaban) is recommended for patients with even one of those. However, it is not clear whether 30 mg/day of edoxaban is adequate for patients with multiple dose adjustment factors. We thus investigated the association between the number of the dose adjustment factors and bleeding risk in patients receiving edoxaban.. We retrospectively analysed 198 patients who received 30 mg/day of edoxaban between April 2015 and March 2017 with follow-up for 1 year.. The incidences of major bleeding were 1.4%, 7.3% and 20.0% in patients with 0-1, 2 and 3 dose adjustment factors, respectively. The Cox proportional hazards regression model revealed that the risk of major bleeding was higher in patients with 2 (hazard ratio [HR]: 5.80, 95% confidence interval [CI]: 0.96-44.05, P = .055) or 3 (HR: 17.70, 95% CI: 2.12-147.70, P = .012) dose adjustment factors than in those with 0-1 dose adjustment factor.. This is the first study to evaluate the risk of bleeding in patients administered 30 mg/day of edoxaban based on the number of dose adjustment factors in clinical practice. For patients receiving edoxaban, as the number of the dose adjustment factors increases, the risk of major bleeding is elevated. In patients with multiple dose adjustment factors, not only one level of dose reduction, but further dose reductions may be considered. Further studies with a larger sample size are needed to confirm these findings.

Topics: Aged; Aged, 80 and over; Creatinine; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Female; Follow-Up Studies; Hemorrhage; Humans; Incidence; Male; Middle Aged; Pyridines; Retrospective Studies; Risk; 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

Edoxaban is used to prevent and treat stroke or systemic embolism such as venous thromboembolism. Although bleeding is the most common complication of anticoagulants, only a few studies have addressed the safety of direct oral anticoagulants in East Asian patients. In this study, we investigated the risk factors for bleeding in Japanese patients receiving edoxaban. A retrospective review of the records of 198 patients who received 30 mg/d edoxaban in our hospital between April 2015 and March 2017 was performed. Subsequently, these patients were followed up to 1 year. Seven (3.5%) and 22 (11.1%) patients developed major bleeding and clinically relevant bleeding, respectively. In the univariate Cox regression analyses, low baseline hemoglobin levels (p = 0.002) and low baseline creatinine clearance (p = 0.020) were significantly associated with major bleeding. Multivariate Cox regression analysis revealed that a low baseline hemoglobin level was a significant risk factor for major bleeding and clinically relevant bleeding [hazard ratio 1.67 per 1 g/dL decrease (95% confidence interval 1.14-2.56, p = 0.008) and hazard ratio 1.31 per 1 g/dL decrease (95% confidence interval 1.06-1.62, p = 0.013), respectively]. Baseline hemoglobin level in quartiles also showed a quartile-dependent decrease in major bleeding and clinically relevant bleeding event. These results suggest that low baseline hemoglobin level is a significant risk factor for both major bleeding and clinically relevant bleeding in Japanese patients receiving edoxaban. Thus, these patients should be carefully monitored.

Topics: Aged; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Japan; Male; Middle Aged; Pyridines; Retrospective Studies; Risk Factors; Thiazoles

Antiviral drugs are administered in patients with severe COVID-19 respiratory syndrome, including those treated with direct oral anticoagulants (DOACs). Concomitant administration of antiviral agents has the potential to increase their plasma concentration. A series of patients managed in the Cremona Thrombosis Center were admitted at Cremona Hospital for SARS-CoV-2 and started antiviral drugs without stopping DOAC therapy. DOAC plasma levels were measured in hospital and results compared with those recorded before hospitalization.. All consecutive patients on DOACs were candidates for administration of antiviral agents (lopinavir, ritonavir, or darunavir). Plasma samples for DOAC measurement were collected 2to 4 days after starting antiviral treatment, at 12 hours from the last dose intake in patients on dabigatran and apixaban, and at 24 hours in those on rivaroxaban and edoxaban. For each patient, C-trough DOAC level, expressed as ng/mL, was compared with the one measured before hospitalization.. Of the 1039 patients hospitalized between February 22 and March 15, 2020 with COVID-19 pneumonia and candidates for antiviral therapy, 32 were on treatment with a DOAC. DOAC was stopped in 20 and continued in the remaining 12. On average, C-trough levels were 6.14 times higher during hospitalization than in the pre-hospitalization period.. DOAC patients treated with antiviral drugs show an alarming increase in DOAC plasma levels. In order to prevent bleeding complications, we believe that physicians should consider withholding DOACs from patients with SARS-CoV-2 and replacing them with alternative parenteral antithrombotic strategies for as long as antiviral agents are deemed necessary and until discharge.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antithrombins; Antiviral Agents; Betacoronavirus; Coronavirus Infections; COVID-19; Dabigatran; Darunavir; Drug Interactions; Drug Monitoring; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Italy; Lopinavir; Male; Pandemics; Patient Safety; Pneumonia, Viral; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Risk Factors; Ritonavir; SARS-CoV-2; Severity of Illness Index; Thiazoles

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

Guidance for periprocedural anticoagulant management is mainly based on limited data from Phase III or observational studies and expert opinion.. EMIT-AF/VTE was designed to document the risks of bleeding and thromboembolic events in more than 1000 patients on edoxaban undergoing diagnostic and therapeutic procedures in clinical practice.. Routine care in a multinational multicenter, prospective observational study. Participants were adult patients with atrial fibrillation and/or venous thromboembolism treated with edoxaban for stroke prevention or for secondary prevention in venous thromboembolic disease, undergoing a wide range of diagnostic and therapeutic procedures. Edoxaban therapy was interrupted periprocedurally at the treating physician's discretion. Patients were evaluated from 5 days pre- until 30 days postprocedure. Primary outcome was the incidence of International Society on Thrombosis and Haemostasis defined major bleeding; secondary outcomes included incidence of clinically relevant non-major bleeding, acute coronary syndrome, and acute thromboembolic events.. Outcomes and management are reported for the first procedures in 1155 unselected patients. Five cases of major bleeding (0.4%) and eight of clinically relevant non-major bleeding (0.7%) were documented, five (38%) of which occurred outside the period of likely edoxaban effect (last edoxaban dose ≥3 days prior to bleeding). Five (0.4%) deaths from any cause, seven acute thromboembolic events (0.6%) including two cardiac deaths (0.2%) in six patients, and one acute coronary event (0.1%) occurred.. The periprocedural bleeding and acute thromboembolic event risks for patients treated with edoxaban were low. This can help inform both clinical routine and guidelines for the periprocedural management of edoxaban.

Topics: Adult; Anticoagulants; Atrial Fibrillation; Catheter Ablation; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Perioperative Period; Prospective Studies; Pyridines; Thiazoles; Thromboembolism; Treatment Outcome

The present article addresses clinical challenges associated with the choice of the anticoagulant agent, the definition of the duration of anticoagulant treatment and the assessment of the risk-to-benefit ratio of prolonged anticoagulation for patients with pulmonary embolism (PE).Anticoagulation is performed with unfractionated heparin (UFH) in hemodynamically unstable patients and with low molecular weight heparins (LWMH) or fondaparinux in normotensive patients. In patients with high or intermediate clinical probability of pulmonary embolism, anticoagulation should be initiated without delay while awaiting the results of diagnostic tests. LMWH and fondaparinux are preferred over UFH in the initial anticoagulation of PE since they are associated with a lower risk of bleeding.All patients with PE require therapeutic anticoagulation for at least three months. The current 2019 guidelines of the European Society of Cardiology (ESC) recommend that all eligible patients should be treated with a non-vitamin K antagonist oral anticoagulant (NOAC) in preference to a vitamin K antagonist (VKA). In patients with active cancer, Apixaban, Edoxaban and Rivaroxaban are effective alternatives to treatment with LMWH.The decision on the duration of anticoagulation should consider both, the individual risk of PE recurrence and the individual risk of bleeding. The risk for recurrent PE after discontinuation of treatment is related to the features of the index PE event. While patients with a strong transient risk factor have a low risk of recurrence and anticoagulation can be discontinued after three months, patients with strong persistent risk factor (such as active cancer) have a high risk of recurrence and thus should receive anticoagulant treatment of indefinite duration. Given the favourable safety profile of NOACs (especially if a reduced dosage of Apixaban or Rivaroxaban is initiated after at least six months of therapeutic anticoagulation), extended oral anticoagulation of indefinite duration should be considered for all patients with intermediate risk of recurrence.

Topics: Acute Disease; Dalteparin; Dose-Response Relationship, Drug; Drug Administration Schedule; Fibrinolytic Agents; Fondaparinux; Guideline Adherence; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Long-Term Care; Neoplasms; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Recurrence; Risk Assessment; Risk Factors; Rivaroxaban; Thiazoles

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

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

Edoxaban is an orally administered anticoagulant treatment that is used in patients with cerebral infarction, venous thrombosis, or other conditions, with a reported incidence of gastrointestinal hemorrhage at approximately 1%. We encountered the rare case of a patient who developed a gallbladder hemorrhage after the administration of edoxaban.. Our case suggests that gallbladder hemorrhage needs to be considered a possible complication for patients on direct oral anticoagulants.

Topics: Administration, Oral; Aged, 80 and over; Anticoagulants; Cholecystectomy, Laparoscopic; Endoscopy; Female; Gallbladder Diseases; Hemorrhage; Humans; Melena; Pyridines; Thiazoles; Tomography, X-Ray Computed

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

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

Clinical outcomes of the real-world Asian nonvalvular atrial fibrillation (NVAF) patients treated with DOAC and the incremental bleeding risk of add-on antiplatelet therapy to direct oral anticoagulants (DOACs) are still to be investigated. We conducted a single-center prospective observational registry of NVAF patients treated with DOACs: the DIRECT registry (UMIN000033283). All patients with NVAF (N = 2216) who were users of dabigatran (N = 648), rivaroxaban (N = 538), apixaban (N = 599), or edoxaban (N = 431) from June 2011 to November 2017 were enrolled (71.6 ± 10.8 years, 36.4% female, follow-up duration: 407.2 ± 388.3 days). No add-on antiplatelet agent was prescribed to 1,739 patients, while single and dual antiplatelet therapy (SAPT and DAPT) in combination with DOAC were prescribed to 411 and 66 patients, respectively. The primary safety endpoint was any bleeding which was defined as a composite of major bleeding according to the International Society on Thrombosis and Hemostasis criteria and clinically relevant non-major bleeding. Patients treated with add-on antiplatelet agents irrespective of SAPT or DAPT had a higher any-bleeding risk than those without (hazard ratio: 1.42; 95% confidence interval 1.16-1.74, p = 0.001). Multivariate adjusted hazard of add-on antiplatelet therapy was not statistically significant (hazard ratio: 1.20; 95% confidence interval 0.94-1.53, p = 0.147). In conclusion, NVAF patients treated with antiplatelet agents and DOAC had a significantly higher bleeding risk than those using DOAC only. However, after adjustment of patients' background, add-on antiplatelet therapy to DOAC itself did not influence to a bleeding risk.

Topics: Administration, Oral; Aged; Antithrombins; Atrial Fibrillation; Dabigatran; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Follow-Up Studies; Hemorrhage; Humans; Incidence; Japan; Male; Middle Aged; Platelet Aggregation Inhibitors; Prognosis; Prospective Studies; Pyrazoles; Pyridines; Pyridones; Registries; Rivaroxaban; 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

Direct oral anticoagulants (DOACs) are safe and efficacious when compared to warfarin for patients with venous thromboembolism (VTE). However, bleeding is a major side effect of anticoagulant therapy in VTE patients. Discontinuation of the DOACs associated to adverse events such as bleeding. The HAS-BLED score predicts warfarin-associated hemorrhage. However, little is known about risk factors for DOAC-associated minor bleeding in VTE patients. We aimed to identify risk factors for minor bleeding in VTE patients that were treated with edoxaban, rivaroxaban, or apixaban. We retrospectively evaluated the data of 212 VTE patients who received treatment with a DOAC. The study endpoint was defined as the occurrence of minor bleeding. Logistic regression analysis was used to determine risk factors that were significantly associated with minor bleeding. A total of 36 (17.0%) patients experienced minor bleeding, with rates of 15.7%, 0%, and 21.3% for edoxaban, rivaroxaban, and apixaban, respectively. In the multivariate analysis, bleeding history or predisposition [odds ratio (OR) 6.083, 95% confidence interval (CI) 2.131-17.364, p=0.001] and cancer (OR 6.397, 95% CI 2.858-14.317, p<0.001) were significantly associated with minor bleeding. Bleeding history or predisposition and cancer were the most important risk factors for DOAC-induced minor bleeding in VTE patients in this study. To continue anticoagulant therapy of the DOACs, further management systems by minor bleeding risk factors for patients with VTE will be required.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Cohort Studies; Female; Hemorrhage; Humans; Male; Middle Aged; Multivariate Analysis; Neoplasms; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Risk Factors; Rivaroxaban; Severity of Illness Index; Thiazoles; Venous Thromboembolism

A male patient diagnosed with severe congenital protein C (PC) deficiency during the neonatal period was treated with long-term warfarin but frequently developed purpura fulminans and bleeding. At four years of age, edoxaban was initiated (direct oral anticoagulant [DOAC]). His d-dimer and fibrin/fibrinogen degradation product levels were closely monitored. His PC activity increased from below the sensitivity range to 17%; this increase was thought to be due to a reduction in PC consumption during edoxaban therapy. After edoxaban introduction, he experienced just one episode of purpura fulminans over two years without any adverse events. Thus, DOAC may be a promising alternative for the management of congenital PC deficiency.

Topics: Child, Preschool; Disease Management; Factor Xa Inhibitors; Hemorrhage; Humans; Male; Prognosis; Protein C Deficiency; Purpura Fulminans; Pyridines; Thiazoles

It is unclear whether the two once-daily dosing non-vitamin K antagonist oral anticoagulants (NOACs), edoxaban and rivaroxaban, have similar effectiveness and safety in Asian patients with non-valvular atrial fibrillation (AF). This study aimed to compare the effectiveness and safety of edoxaban and rivaroxaban in a Korean population with non-valvular AF. Using the Korean National Health Insurance Service database from January 2014 to December 2016, we compared the risk of ischemic stroke, intracranial hemorrhage (ICH), hospitalization for gastrointestinal (GI) bleeding, hospitalization for major bleeding, all-cause death, and composite outcome in a 3:1 propensity score matched cohort in patients with AF who were naïve to rivaroxaban (n = 12,369) and edoxaban (n = 4,123). Hazard ratios for the six clinical outcomes were analyzed using Cox regression analysis with rivaroxaban as the reference. Baseline characteristics were balanced between the two groups (median age, 71 years; median CHA

Topics: Administration, Oral; Aged; Aged, 80 and over; Asian People; Atrial Fibrillation; Cause of Death; Disease Susceptibility; Drug Administration Schedule; Factor Xa Inhibitors; Female; Flow Cytometry; Follow-Up Studies; Hemorrhage; Humans; Incidence; Infant; Male; Middle Aged; Patient Outcome Assessment; Population Surveillance; Pyridines; Rivaroxaban; 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

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

To evaluate the use of direct-acting oral anticoagulants in patients with cancer and venous thromboembolism (VTE) treated at Ochsner Medical Center with the intent of determining the efficacy and safety of these agents.. Patients were identified by a retrospective data extraction of patients treated at Ochsner Medical Center from January 1, 2013, through December 31, 2015. Patients were included for review if they were ≥18 years of age, with a confirmed diagnosis of VTE and active or history of cancer, and if they received dabigatran, apixaban, rivaroxaban, or edoxaban for at least 6 months. The primary objectives were the rate of recurrence of VTE and the incidence of bleeding at 6 months.. Thirty-seven patients were identified. Twelve patients were diagnosed with PE, 21 with DVT, 3 with DVT and PE, and 1 with DVT and superficial vein thrombosis (SVT). Apixaban was used most often (n = 27). No patients experienced a recurrent DVT or PE at 6 months. Two patients experienced adverse effects during treatment.. In this single-center, retrospective, observational study in patients with cancer receiving DOAC therapy, there were no episodes of recurrent VTE and only 2 episodes of clinically significant bleeding.

Topics: Administration, Oral; Aged; Anticoagulants; Cohort Studies; Dabigatran; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Neoplasms; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Rivaroxaban; Thiazoles; Venous Thromboembolism

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

Topics: Animals; Antifibrinolytic Agents; Factor Xa Inhibitors; Hemorrhage; Male; Pyridines; Rats, Sprague-Dawley; Thiazoles; Tranexamic Acid

Increasing use of factor Xa (FXa) inhibitors necessitates effective reversal agents to manage bleeding. Andexanet alfa, a novel modified recombinant human FXa, rapidly reverses the anticoagulation effects of direct and indirect FXa inhibitors.. To evaluate the ability of andexanet to reverse anticoagulation in vitro and reduce bleeding in rabbits administered edoxaban.. In vitro studies characterized the interaction of andexanet with edoxaban and its ability to reverse edoxaban-mediated anti-FXa activity. In a rabbit model of surgically induced, acute hemorrhage, animals received edoxaban vehicle+andexanet vehicle (control), edoxaban (1 mg/kg)+andexanet vehicle, edoxaban+andexanet (75 mg, 5-minute infusion, 20 minutes after edoxaban), or edoxaban vehicle+andexanet prior to injury.. Andexanet bound edoxaban with high affinity similar to FXa. Andexanet rapidly and dose-dependently reversed the effects of edoxaban on FXa activity and coagulation pharmacodynamic parameters in vitro. In edoxaban-anticoagulated rabbits, andexanet reduced anti-FXa activity by 82% (from 548±87 to 100±41 ng/ml; P<0.0001), mean unbound edoxaban plasma concentration by ~80% (from 100±10 to 21±6 ng/ml; P<0.0001), and blood loss by 80% vs. vehicle (adjusted for control, 2.6 vs. 12.9 g; P = 0.003). The reduction in blood loss correlated with the decrease in anti-FXa activity (r = 0.6993, P<0.0001) and unbound edoxaban (r = 0.5951, P = 0.0035).. These data demonstrate that andexanet rapidly reversed the anticoagulant effects of edoxaban, suggesting it could be clinically valuable for the management of acute and surgery-related bleeding. Correlation of blood loss with anti-FXa activity supports the use of anti-FXa activity as a biomarker for assessing anticoagulation reversal in clinical trials.

Topics: Animals; Anticoagulants; Antidotes; Blood Coagulation; Disease Models, Animal; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Male; Pyridines; Rabbits; Recombinant Proteins; Thiazoles

This study was conducted to describe the real-world hospital length of stay in patients treated with all of the U.S. Food and Drug Administration approved direct oral anticoagulants (DOACs) versus warfarin for new-onset venous thromboembolism (VTE) at a large, tertiary, academic medical center. A retrospective cohort analysis of all adult patients diagnosed with acute onset VTE was conducted. Of the 441 patients included, 261 (57%) patients received DOACs versus 180 (41%) patients received warfarin. In the DOAC group, a total of 92 (35%) patients received rivaroxaban, followed by 83 (32%) patients received apixaban, 50 (19%) patients received dabigatran, and 36 (14%) patients received edoxaban. Patients initiated on DOACs had a statistically significant shorter hospital length of stay compared to patients initiated on warfarin (median 3 days, [IQR 0-5] vs. 8 days [IQR 5-11], P < 0.05). Despite the shorter hospital length of stay in patients receiving DOACs, the overall reported differences between the DOACs group and the warfarin group in terms of recurrent VTE, major bleeding, intracranial bleeding, and gastrointestinal bleeding at 3 and 6 months were deemed to be statistically insignificant.

Topics: Adult; Aged; Anticoagulants; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Length of Stay; Male; Middle Aged; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Rivaroxaban; Thiazoles; Venous Thromboembolism; Warfarin

Venous thromboembolism (VTE) is a frequent and serious complication of cancer. The current guidelines in the USA and Europe recommend low-molecular weight heparin (LMWH) for the treatment of cancer-associated VTE. In Japan, LMWH is not given for the treatment of VTE; instead edoxaban, an oral direct factor Xa inhibitor, was approved for the treatment of VTE in September 2014. However, the efficacy and safety of the factor Xa inhibitor in cancer patients have not been fully elucidated.. Patients' charts were reviewed retrospectively, and 125 VTE patients (61 cancer patients) in whom edoxaban therapy was started between September 2014 and September 2016 were included in this study. Patients' demographics, changes in VTE amount, VTE recurrence, clinically relevant bleeding, and outcomes until February 2017 were examined.. Patients' characteristics, including age, sex, weight, creatinine clearance, and duration of administration of edoxaban were comparable between cancer and non-cancer patients. No parenteral anticoagulant pretreatment before edoxaban was given in 37.5% and 55.7% of non-cancer and cancer patients, respectively. The incidence of pulmonary embolism was also similar in the two groups. The amount of thrombosis decreased ("improved") or disappeared ("normalized") in 89.6% and 94.1%, respectively, of non-cancer and cancer patients who underwent at least two imaging tests. The frequencies of recurrence of VTE and clinically relevant bleeding were not significantly different between the two groups (p=0.414 and 0.516, respectively). However, 21 cancer patients died, 17 of whom died of cancer, while none of the non-cancer patients died.. The present study showed that the efficacy and safety of edoxaban for the treatment of VTE is comparable between cancer and non-cancer patients. Edoxaban may be a clinically useful therapy for VTE in Japanese cancer patients.

Topics: Aged; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Japan; Male; Middle Aged; Neoplasms; Pulmonary Embolism; Pyridines; Recurrence; Retrospective Studies; Thiazoles; Venous Thromboembolism

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

Topics: Administration, Oral; Anticoagulants; Antithrombins; Dabigatran; Dalteparin; Factor Xa Inhibitors; Hemorrhage; Humans; Multicenter Studies as Topic; Neoplasms; Observational Studies as Topic; Patient Acceptance of Health Care; Prospective Studies; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Recurrence; Rivaroxaban; Thiazoles; Venous Thromboembolism; Venous Thrombosis

Clinical variables including hypertension could be linked with major bleeding events and death beyond vitamin K antagonist (warfarin) or direct oral anti-coagulants (DOACs) treatment strategy.. Subgroup analysis of major bleeding (primary endpoint) associated with clinical variables, site of bleeding, ongoing antithrombotics, reversal treatment or blood transfusion, outcomes (secondary endpoints) was performed in patients with bleeding events submitted to hard 5:1 propensity-score matching for hypertension.. Enrolled patients were 2,792 (mean age, 65.6 ± 19.9 years) during 2-year survey including 166,000 visits, of 200,000 inhabitants catchment area; 8,239 patients received warfarin and 3,797 DOACs. Hypertension account for 1,077 (39%) patients; major bleeding for 474 (17%); death for 29 (1%), and 72 (3%) on 1-month and 1-year, respectively. Hypertension, age, glucose, cancer, ischemic vascular disease, and CHA2D2VASc score were more likely to link with major bleeding. On multivariate analysis, only age (odds ratio [OR], 1.02; P < 0.001), CHA2DS2VASc score ≥ 2 (OR, 2.14; P = 0.001), and glucose (OR, 1.01; P = 0.005) were predictors of major bleeding. Kaplan-Meier analysis demonstrated patients with hypertension as compared with patients without showed 60% versus 20% death on 1-month (P < 0.001). Warfarin compared with DOACs was more likely to present with major bleeding (0.7% versus 0.2%; OR, 2.8; P = 0.005). Receiver operator characteristics analysis showed high value (0.61) of age and glucose over creatinine and systolic arterial pressure (P = NS).. Four in 10 patients with major bleeding showed hypertension; of these 8 in 10 will die within 1 month. Warfarin compared with DOACs was more likely to present with major bleeding.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Blood Glucose; Blood Transfusion; Cardiovascular Diseases; Creatinine; Dabigatran; Emergency Service, Hospital; Epistaxis; Female; Gastrointestinal Hemorrhage; Hematuria; Hemoptysis; Hemorrhage; Humans; Hypertension; Intracranial Hemorrhages; Kaplan-Meier Estimate; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Prognosis; Propensity Score; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Severity of Illness Index; Sex Factors; Thiazoles; Warfarin

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

Most clinical practice guidelines recommend low molecular weight heparin for the treatment of venous thromboembolism (VTE) in cancer patients. In the Hokusai VTE Cancer study, 1050 patients with cancer and acute VTE were randomized to oral edoxaban or subcutaneous dalteparin for at least 6 months and up to 12 months. Edoxaban was non-inferior to dalteparin with respect to the composite outcome of recurrent VTE and major bleeding. The rate of recurrent VTE was numerically lower, but the rate of major bleeding was significantly higher with edoxaban. The frequency of severe major bleeding was similar with edoxaban and dalteparin. The difference in major bleeding was mainly driven by a higher rate of upper gastrointestinal bleeding with edoxaban, especially in patients with gastrointestinal cancer. The pilot Select-D study randomized 406 patients with cancer and VTE to rivaroxaban or dalteparin for 6 months. Recurrent VTE was reduced, while both major and clinically relevant non major bleeding were significantly increased with rivaroxaban. Bleeding mostly involved the gastrointestinal tract and occurred in patients with gastroesophageal cancer. While waiting for ongoing studies on direct oral anticoagulants, the results of the Hokusai VTE Cancer suggest that edoxaban may represent a valuable alternative to low molecular weight heparin for the treatment of cancer-associated VTE. In patients with gastrointestinal cancer, the use of edoxaban requires careful benefit-risk weighting, taking into consideration patient's preferences.

Topics: Anticoagulants; Dalteparin; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Practice Guidelines as Topic; Pyridines; Randomized Controlled Trials as Topic; Rivaroxaban; Thiazoles; Venous Thromboembolism

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 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

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Dabigatran; Female; Hemorrhage; Humans; Male; Prognosis; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Secondary Prevention; Thiazoles

Topics: Anticoagulants; Antithrombins; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Neoplasms; Perioperative Care; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Venous Thromboembolism; Venous Thrombosis

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

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

Few data exist to evaluate the safety and efficacy of direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) undergoing cryoballoon ablation (CB-A). This study is aimed to clarify the usefulness of DOACs in patients undergoing CB-A.. The patients (average age; 65.8±11.9 years old, male 69%) were stratified into one of five subsets based on the type of anticoagulation (warfarin, apixaban, dabigatran, rivaroxaban, or edoxaban), and underwent CB-A. A brain MRI was performed in all patients the day after the CB-A for AF. A total of 257 (19 on warfarin, 30 on apixaban, 66 on dabigatran, 81 on rivaroxaban, and 61 on edoxaban) patients met the inclusion criteria.. The incidence of silent cerebral ischemic lesion was 1 (11.1%) patients on warfarin, 5 (33.3%) on apixaban, 8 (27.6%) on dabigatran, 10 (21.3%) on rivaroxaban, and 10 (29.4%) on edoxaban (p=0.17). Major ischemic events occurred in one patient (1.6%) on edoxaban and one (5.3%) on warfarin. Minor bleeding complications occurred in 1 patient (5.3%) on warfarin, 2 (6.7%) on apixaban, 1 (1.2%) on rivaroxaban, 5 (7.6%) on dabigatran, and 2 (3.3%) on edoxaban (p=0.24). Of note, major bleeding complications occurred in 2 patients (3.3%) on apixaban, 1 (1.2%) on rivaroxaban, 1 (1.5%) on dabigatran, 1 (1.6%) on edoxaban, and 2 (10.5%) on warfarin (p<0.05).. Warfarin use significantly increased the risk of serious bleeding, in contrast, CB-A did not place the patients at an increased risk of complications under a DOAC treatment. There were no significant differences regarding preventing embolic events among the DOAC drugs.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Brain; Brain Ischemia; Cryosurgery; Dabigatran; Embolism; Female; Hemorrhage; Humans; Incidence; Magnetic Resonance Imaging; Male; Middle Aged; Postoperative Complications; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; 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

Since first used in 2009, non-vitamin K oral anticoagulants (NOAC) have gained world-wide acceptance. Two groups of NOAC are currently used: the direct thrombin antagonist dabigatran and three direct factor  Xa antagonists apixaban, edoxaban, and ricaroxaban. With their increasing use for prevention of thromboembolism, the probability increases that NOAC-pretreated patients are admitted to emergency departments or intensive care units.The clinical challenge in NOAC preanticoagulated patients is to adequately cope with the given anticoagulated status of such patients. Because of their short half-life, many patients will be adequately treated with a "wait and see" approach, and surgeries and interventions are postponed until anticoagulant activities have totally subsided. In the few cases where immediate action is mandated, based on appropriate risk assessments it can be decided either to take the increased hemorrhagic risk of early intervention or to transfuse factor concentrates like PPSB or FEIBA which can safely reverse the anticoagulant activities of the three factor Xa antagonists (and potentially also of dabigatran). Recently a humanized Fab antibody fragment for dabigatran, idarucizumab, has been introduced onto the market, that can immediately reverse the anticoagulant effects of dabigatran. For the reversal of dabigatran, idarucizumab is therefore the drug of choice.In addition, in some specific indications of emergency and intensive care medicine, the primary use of a NOAC can be considered advantageous. Such indications are early cardioversion in patients admitted for new episodes of atrial fibrillation and patients with acute pulmonary embolism. For the widespread use of low-molecular-weight heparins in such indications, however, the decision to use a NOAC for anticoagulant therapy is frequently postponed to the treatment phase when the stabilized patient is already treated on the general ward.

Topics: Antibodies, Monoclonal, Humanized; Anticoagulants; Dabigatran; Electric Countershock; Emergency Service, Hospital; Factor Xa Inhibitors; Hemorrhage; Humans; Intensive Care Units; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thrombin; Thromboembolism; Vitamin K

Edoxaban is an oral, once-daily direct factor Xa inhibitor. To support the possibility that patients may choose to switch treatment from another nonvitamin K antagonist oral anticoagulant to edoxaban, this clinical study was conducted to evaluate the pharmacokinetic and pharmacodynamic effects of edoxaban after switching from rivaroxaban or dabigatran etexilate to edoxaban.. In this open-label, three-period, crossover study, healthy subjects received 3 days of edoxaban 60 mg daily, rivaroxaban 20 mg daily, or dabigatran etexilate 150 mg twice daily, followed by edoxaban 60 mg on day 4.. Day 4 edoxaban pharmacokinetic parameters were similar for all treatments. The peak effect of edoxaban on prothrombin time (PT) after 4 days of edoxaban only was 21.8 ± 2.46 s; after switching from rivaroxaban to edoxaban, peak effect on PT was similar at 21.8 ± 2.88 s. After switching from dabigatran etexilate to edoxaban, least squares mean activated partial thromboplastin time (aPTT) at 2 h after administration was 47.6 vs 35.0 s for edoxaban alone. The treatment difference was 12.8 s (95% confidence interval 10.5-15.1; p < 0.0001). Post hoc analysis revealed that predose aPTT was elevated on day 3 of dabigatran etexilate administration, and on day 4, indicating a carryover effect from dabigatran. All treatments were well tolerated and there were no safety concerns upon switching, with no increased risk of bleeding.. The study results suggest that switching to edoxaban from either rivaroxaban or dabigatran etexilate at the time of the next dose is well tolerated and maintains coagulation status.

Topics: Administration, Oral; Adult; Anticoagulants; Area Under Curve; Cross-Over Studies; Dabigatran; Drug Substitution; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Pyridines; Rivaroxaban; Thiazoles; Young Adult

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Antithrombins; Blood Loss, Surgical; Cerebral Hemorrhage; Clinical Trials as Topic; Dabigatran; Drug Approval; Emergencies; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiazoles; United States; United States Food and Drug Administration

Patients on direct oral anticoagulants (DOAC) may need interruption of treatment before surgery or invasive procedures. Owing to their favorable pharmacokinetics, DOAC could be interrupted for a fixed number of days before surgery or invasive procedures without laboratory testing. However, there are a number of issues that raise concerns about the safety of this strategy. In contrast, laboratory testing prior to surgery or invasive procedures would provide a direct assessment of the residual drug concentration and minimize the risk of bleeding. This forum is aimed at discussing the pros and cons of the two strategies and fostering discussion on this important issue. Overall, the laboratory strategy appears superior in terms of patient safety and should be considered in patients undergoing surgical or invasive procedures.

Topics: Administration, Oral; Anticoagulants; Blood Coagulation Tests; Factor Xa Inhibitors; Hemorrhage; Humans; Mass Spectrometry; Patient Safety; Preoperative Period; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thrombin; Thrombin Time

Clinical trials of antithrombotic therapy require a cohesive assessment of benefit and risk. A new graphical method to represent the bivariate relation of benefit and risk in trials of antithrombotic drugs is described and illustrated using published data from the four major registration clinical trials of non-vitamin K oral anticoagulants (NOACs) totalling 71,683 patients for prevention of thromboembolic events (TE) in patients with atrial fibrillation (RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE-AF TIMI48). A curve representing a null hypothesis defines a region of benefit on a two-dimensional plane. Trial results are summarised by a rectangle defined by standard 95 % confidence intervals (CI) for thrombosis and bleeding risks. Benefit is judged by whether the confidence rectangle contains the null curve. The treatment effect is measured by the distance from the null curve to the opposing corners of the confidence rectangle (termed "corner distance (CD)"). Across trials NOACs reduced the absolute risk of TE compared to warfarin by 0.30 % (95 % CI: -0.56 % to -0.05 %) and reduced major bleeding by 0.88 % (95 % CI: -1.26 % to -0.51 %). Bivariate evaluation showed NOAC superiority to warfarin overall and elucidated dose differences; low dose edoxaban increased bivariate TE-bleeding risk 0.08 % (CD = -0.85 % to 0.78 %), whereas high dose edoxaban reduced risk 1.41 % (CD = -2.07 % to -0.70 %). In conclusion, bivariate evaluation facilitates visual assessment of the safety-efficacy profile of antithrombotic drugs. Its application to trials in atrial fibrillation found NOACs superior to warfarin without substantial differences between agents.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Clinical Trials, Phase III as Topic; Hemorrhage; Humans; Models, Statistical; Pyridines; Randomized Controlled Trials as Topic; Risk Factors; Thiazoles; Thromboembolism; Warfarin

To determine the potential effect of substituting glomerular filtration rate (GFR) estimates for renal clearance estimated using the Cockcroft-Gault method (CrCL-CG) to calculate direct oral anticoagulant (DOAC) dosing.. Simulation and retrospective data analysis.. Community, academic institution, nursing home.. Noninstitutionalized individuals aged 19 to 80 from the National Health and Nutrition Examination Survey (NHANES) (2011/12) (n = 4,687) and medically stable research participants aged 25 to 105 (n = 208).. Age, height, weight, sex, race, serum creatinine, CrCL-CG, and GFR (according to the Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration equations). Outcome measures were dosing errors if GFR were to be substituted for CrCL-CG.. Renal clearance estimates according to all methods were highly correlated (P < .001), although at lower clearances, substitution of GFR estimates for CrCL-CG resulted in failure to recognize needs for dose reductions of rivaroxaban or edoxaban in 28% of NHANES subjects and 47% to 56% of research subjects. At a CrCL-CG of less than 30 mL/min, GFR estimates missed indicated dosage reductions for dabigatran in 18% to 21% of NHANES subjects and 57% to 86% of research subjects. Age and weight contributed to differences between renal clearance estimates (P < .001), but correction of GFR for body surface area (BSA) did not reduce dosing errors. At a CrCL-CG greater than 95 mL/min, edoxaban is not recommended, and GFR esimates misclassified 24% of NHANES and 39% of research subjects. Correction for BSA reduced misclassification to 7% for NHANES and 14% in research subjects.. Substitution of GFR estimates for estimated CrCl can lead to failure to recognize indications for reducing DOAC dose and potentially higher bleeding rates than in randomized trials.

Topics: Aged; Aged, 80 and over; Anticoagulants; Creatinine; Dabigatran; Dose-Response Relationship, Drug; Drug Dosage Calculations; Female; Glomerular Filtration Rate; Hemorrhage; Humans; Kidney Function Tests; Male; Metabolic Clearance Rate; Nutrition Surveys; Outcome Assessment, Health Care; Pyridines; Renal Elimination; Rivaroxaban; Thiazoles; United States

Edoxaban is an oral, selective direct factor Xa inhibitor approved in Japan for venous thromboembolism prevention after orthopedic surgery. Data are lacking regarding reversal strategies for edoxaban; this study assessed whether four-factor prothrombin complex concentrate (Beriplex/Kcentra; CSL Behring GmbH, Marburg, Germany) can effectively reverse its effects on hemostasis using a previously described rabbit model.. The study comprised assessments of thrombin generation in vitro, pharmacokinetic parameters, and edoxaban reversal in vivo. In a blinded in vivo stage, a standardized kidney incision was performed in animals (n = 11 per group) randomized to receive vehicle + saline, edoxaban (1,200 μg/kg) + saline, or edoxaban (1,200 μg/kg) + four-factor prothrombin complex concentrate (50 IU/kg). Animals were monitored for treatment impact on hemostasis and coagulation parameters. Data are median (range). Statistical tests were adjusted for multiple testing.. Edoxaban administration increased blood loss (30 [2 to 44] ml) and time to hemostasis (23 [8.5 to 30.0] min) compared with the control group (3 [1 to 8] ml and 3 [2.0 to 5.0] min, respectively). Biomarkers of coagulation (prothrombin time, activated partial thromboplastin time, whole blood clotting time) and thrombin generation parameters (e.g., peak thrombin, endogenous thrombin potential, lag time) were also affected by edoxaban. Administration of four-factor prothrombin complex concentrate significantly reduced time to hemostasis (to 8 [6.5 to 14.0] min, observed P < 0.0001) and total blood loss (to 9 [4 to 22] ml, observed P = 0.0050) compared with the edoxaban + saline group. Of the biomarkers tested, prothrombin time, whole blood clotting time, and endogenous thrombin potential correlated best with clinical parameters.. In a rabbit model of hemostasis, four-factor prothrombin complex concentrate administration significantly decreased edoxaban-associated hemorrhage.

Topics: Acute Disease; Animals; Blood Coagulation Factors; Blood Coagulation Tests; Chinchilla; Endpoint Determination; Female; Hemorrhage; Hemorrhagic Disorders; Hemostatics; In Vitro Techniques; Pyridines; Rabbits; Thiazoles; Thrombin

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: Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Drug Monitoring; Drug Substitution; Half-Life; Hemorrhage; Humans; Kidney Function Tests; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Thromboembolism; Warfarin

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

DOACs are a new group of blood-thinner medications that may have some advantages over warfarin. A health care provider will look at several different factors to help patients decide if a DOAC is a good choice. Patients taking DOACs should discuss medication changes, a plan for taking the DOAC before and after a surgery, and any bleeding side effects with their health care provider.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Blood Coagulation; Dabigatran; Drug Costs; Drug Monitoring; Factor Xa Inhibitors; Hemorrhage; Humans; International Normalized Ratio; Patient Selection; Pyrazoles; Pyridines; Pyridones; Risk Factors; Rivaroxaban; Thiazoles

Venous thromboembolism (VTE) is associated with almost 300,000 deaths per year in the United States. Novel oral anticoagulants (NOACs) offer an alternative to warfarin-based therapy without monitoring requirements and with fewer drug and food interactions. Edoxaban, a direct Xa inhibitor, is approved by the Food and Drug Administration (FDA), based upon results of the Hokusai-VTE Phase 3 trial. The trial demonstrated that edoxaban administered once daily after initial treatment with heparin was non-inferior in reducing the risk of VTE recurrence and caused significantly less major and clinically relevant non-major (CRNM) bleeding compared to warfarin. The objective of this study was to evaluate the cost-effectiveness of edoxaban versus warfarin for the treatment of adults with VTE.. A cost-effectiveness model was developed using patient-level data from the Hokusai-VTE trial, clinical event costs from real-world databases, and drug acquisition costs for warfarin of $0.36 and edoxaban of $9.24 per tablet.. From a U.S. health-care delivery system perspective, the incremental cost-effectiveness ratio (ICER) was $22,057 per quality adjusted life year (QALY) gained. Probabilistic sensitivity analysis showed that edoxaban had an ICER <$50,000 per QALY gained relative to warfarin in 67% of model simulations. The result was robust to variation in key model parameters including the cost and disutility of warfarin monitoring.. Despite its higher drug acquisition cost, edoxaban is a cost-effective alternative to warfarin for the treatment of VTE.

Topics: Adult; Anticoagulants; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Drug Administration Schedule; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Pyridines; Randomized Controlled Trials as Topic; Thiazoles; Treatment Outcome; Venous Thromboembolism; Warfarin

Topics: Blood Coagulation Factors; Drug Monitoring; Factor Xa Inhibitors; Hemorrhage; Humans; Pyridines; Thiazoles

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

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

The direct thrombin inhibitor, dabigatran, as well as the direct factor Xa inhibtors rivaroxaban, apixaban, and edoxaban, display pharmacodynamic features quite similar to low-molecular-weight heparins, with a time to peak level of 1-4 hours after oral administration, and a half-life between 5 and 14 hours. All drugs display a linear relationship and a high degree of correlation between drug levels in plasma, and the anticoagulant effect. Major differences are the extent of renal elimination (with 80% or more for dabigatran, 66% for rivaroxaban [33% unchanged, active drug, and 33% inactive metabolites], 33% for edoxaban, and finally, 25% for apixaban), and bioavailability, which determines the amount of drug required for attaining the target plasma concentration of the drug. Due to the reliable pharmacokinetics and pharmacodynamics, no routine laboratory monitoring is necessary, although dedicated laboratory assays are available for emergencies and some other specific conditions.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Drug Interactions; Drug Monitoring; Half-Life; Hemorrhage; Humans; Kidney; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Thromboembolism

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

This study evaluated differences in medical costs associated with clinical end-points from randomized clinical trials that compared the new oral anticoagulants (NOACs), dabigatran, rivaroxaban, apixaban, and edoxaban, to standard therapy for treatment of patients with venous thromboembolism (VTE).. Event rates of efficacy and safety end-points from the clinical trials (RE-COVER, RE-COVER II, EINSTEIN-Pooled, AMPLIFY, Hokusai-VTE trial) were obtained from published literature. Incremental annual medical costs among patients with clinical events from a US payer perspective were obtained from the literature or healthcare claims databases and inflation adjusted to 2013 costs. Differences in total medical costs associated with clinical end-points for the NOACs vs standard therapy were then estimated. One-way and Monte Carlo sensitivity analyses were carried out.. A lower rate of major bleedings was associated with use of any of the NOACs vs standard therapy. Except for dabigatran, use of NOACs was also associated with a lower rate of recurrent VTE/death. As a result of the reduction in clinical event rates, the overall medical cost differences were -$146, -$482, -$918, and -$344 for VTE patients treated with dabigatran, rivaroxaban, apixaban, and edoxaban, respectively, vs patients treated with standard therapy.. When any of the four NOACs are used instead of standard therapy for acute VTE, treatment medical costs are reduced. Apixaban is associated with the greatest reduction in medical costs, which is driven by medical cost reductions associated with both efficacy and safety end-points. Further evaluation may be needed to validate these results in the real-world setting.

Topics: Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Fees, Pharmaceutical; Health Expenditures; Hemorrhage; Humans; Models, Econometric; Monte Carlo Method; Morpholines; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiazoles; Thiophenes; Venous Thromboembolism

Edoxaban is an oral, once-daily, selective, direct factor Xa inhibitor approved in Japan for the prevention of venous thromboembolism following major orthopedic surgery. Currently, edoxaban is in Phase III clinical development for the prevention of stroke and systemic embolic events in patients with atrial fibrillation, and for the treatment and prevention of recurrences of venous thromboembolism. This report describes the adverse drug reactions (ADRs) spontaneously reported during early postmarketing phase vigilance from the time of its commercial launch in Japan.. All spontaneously reported ADRs following edoxaban use received by Daiichi Sankyo during early postmarketing phase vigilance from July 19, 2011, to January 18, 2012, were entered into the safety database and included in this review. Approximately 20,000 patients were estimated to have been treated with edoxaban.. The mean age of patients was 74.2 years, their mean weight was 59.4 kg, and approximately 70% were female. A total of 67 ADRs were reported in 56 patients, of which the majority included bleeding events (51 ADRs in 42 patients). Of these, 15 ADRs (in 14 patients) were serious, including cerebral hemorrhage (n = 1), gastric hemorrhage (n = 2; gastric hemorrhage [n = 1] and gastric ulcer hemorrhage [n = 1]), and surgical-site hemorrhage (n = 12; hemorrhage [n = 6], subcutaneous hemorrhage [n = 3], wound hemorrhage [n = 2], and wound hematoma [n = 1]). Most ADRs occurred within the first week of treatment and there were no fatalities. Nonserious ADRs associated with bleeding that occurred in >1 patient included subcutaneous hemorrhage (n = 9), wound hemorrhage (n = 5), postprocedural hematoma (n = 4), anemia (n = 4), and hemarthrosis (n = 3). Other nonserious ADRs not associated with bleeding and occurring in >1 patient included abnormal hepatic function (n = 4) and diarrhea (n = 2).. Safety data from the first 6 months of postmarketing experience with edoxaban did not identify any unforeseen safety signals, consistent with the known safety profile of edoxaban.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Aged; Anticoagulants; Female; Hemorrhage; Humans; Japan; Male; Middle Aged; Orthopedic Procedures; Pyridines; Risk Factors; Thiazoles; Time Factors; Treatment Outcome; Venous Thromboembolism

Topics: Administration, Oral; Anticoagulants; Hemorrhage; Humans; Pulmonary Embolism; Pyridines; Randomized Controlled Trials as Topic; Secondary Prevention; Thiazoles; Venous Thrombosis; Vitamin K; Warfarin

Edoxaban, an oral, direct factor Xa inhibitor, has a similar or low incidence of bleeding events compared with other anticoagulants in clinical trials. Therefore, agents to reverse the anticoagulant effects of edoxaban could be desirable in emergency situations. In this study, the reversal effects of haemostatic agents were determined on prothrombin time (PT) prolongation in vitro and bleeding time prolongation in vivo by edoxaban. PT using human plasma was measured in the presence of edoxaban at therapeutic and excess concentrations with the haemostatic agents, prothrombin complex concentrate (PPSB-HT), activated prothrombin complex concentrate (Feiba), and recombinant factor VIIa (rFVIIa). In rats, rFVIIa and Feiba was given during intensive anticoagulation with edoxaban. The haemostatic effect was evaluated in a model of planta template bleeding and a potential prothrombotic effect was evaluated in a venous thrombosis model. PPSB-HT, Feiba, and rFVIIa concentration-dependently shortened PT prolonged by edoxaban. Among these, rFVIIa and Feiba showed potent activities in reversing the PT prolongation by edoxaban. rFVIIa (1 and 3 mg/kg, i.v.) and Feiba (100 U/kg, i.v.) significantly reversed edoxaban (1 mg/kg/h)-induced prolongation of bleeding time in rats. In a rat venous thrombosis model, no potentiation of thrombus formation was observed when the highest dose (3 mg/kg) of rFVIIa was added to edoxaban (0.3 and 1 mg/kg/h) compared with the control. The present study indicated that rFVIIa, Feiba, and PPSB-HT have the potential to be reversal agents for edoxaban.

Topics: Administration, Oral; Animals; Anticoagulants; Blood Coagulation Factors; Factor VIIa; Factor Xa Inhibitors; Hemorrhage; Hemostasis; Humans; Male; Prothrombin Time; Pyridines; Rats; Rats, Inbred Strains; Thiazoles