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Direct (New-generation) Oral Anticoagulants (DOACs) have emerged as effective agents which are used in place of vitamin-K antagonists in treatment and prophylaxis of Venous Thromboembolism (VTE), atrial fibrillation and other thrombotic diseases. Among them, the FIIa- direct thrombin inhibitor dabigatran and FXa inhibitors (rivaroxaban, apixaban, edoxaban) are the most broadly used. Anticoagulant dosing may differ under special considerations. The patients’ physiological reserves, organ functional status and failures should be taken into account in clinical decision-making processes. The advantages and drawbacks of each specific agent should be weighed with special regard to metabolism, pharmacokinetics and pharmacodynamics, along with the efficiency of the agents in different indications. This article aims to review the most recent literature to highlight the usage and efficacy of the agents in different clinical conditions.

Background and purpose Hypertension is common in patients with atrial fibrillation (AF) and carries an additional risk for complications, most notably stroke and bleeding. We assessed the history of hypertension, level of blood pressure control, and an interaction with the choice of oral anticoagulants on clinical outcomes. Methods We performed a systematic review and meta-analysis of studies that randomised patients to novel oral anticoagulants (NOACs) or vitamin K antagonists (VKAs) and reported outcomes stratified by presence of hypertension. Collected outcomes were: ischaemic stroke or systemic embolism (SE), haemorrhagic stroke, intracranial haemorrhage and major bleeding. Log adjusted hazard ratios (HR) and corresponding standard error were calculated, and HRs were compared using Mantel-Haenszel random effects. Quality of the evidence was assessed with Cochrane risk of bias tool. Results Five high-quality studies were eligible, including 71.527 participants who received NOACs (apixaban, dabigatran, edoxaban, rivaroxaban) or VKAs, with median follow-up of 1.8-2.8 years. Compared with patients without hypertension, those with hypertension had higher adjusted risk for ischaemic stroke/SE (HR: 1.25, 95%-CI:1.09, 1.43) and haemorrhagic stroke (HR:1.98, 1.24-3.16). On a continuous scale, the risk of ischaemic stroke/SE increased 6-7% per 10 mmHg increase in systolic blood pressure. No interactions were found between the efficacy or safety of NOACs versus VKAs in the presence or absence of hypertension. In both groups, the use of NOACs led to a lower risk of ischaemic stroke/SE, haemorrhagic stroke and intracranial haemorrhage compared with patients that used VKAs. Conclusions Adequate blood pressure management is vital to optimally reduce the risk of stroke in patients with atrial fibrillation. The benefits of NOACs over VKAs, also apply to patients with elevated blood pressure.

Background Separation gels are often used in collection tubes, but adsorption of drugs onto the gel may cause falsely low concentrations in therapeutic drug monitoring. In this study, the stability of apixaban, edoxaban, rivaroxaban, flecainide, amiodarone, and desethylamiodarone was assessed in tubes, with and without gel separators. Methods Drug-free blood was spiked and stored for up to 7 d in non-gel tubes and gel tubes from two manufacturers (Vacuette and Vacutainer). The samples were analyzed in triplicates using ultra high pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Results At ambient temperature conditions, the serum concentrations of apixaban, edoxaban, and rivaroxaban in a tube with acrylic-based gel had already decreased at baseline, while it took 6 h to observe the same result in a tube with olefin-based gel. At 4 °C, the reduction in serum concentration was considerably slower. For flecainide, the gel tube concentrations were stable at ambient temperature for 3 d, but decreased after 7 d in acrylic-based gel tubes. Amiodarone and desethylamiodarone stored in gel tubes at 4 °C showed decrease in concentrations after 24 h and 6 h, respectively. Conclusion Acrylic-based gel tubes should not be used for any of the tested drugs. Although olefin-based gel tubes may be used for anticoagulants and flecainide, it is advisable to prefer non-gel tubes as a general precaution.

Hypercoagulability associated with malignant tumors causes thrombosis, termed Trousseau's syndrome, but is rarely associated with benign gynecological tumors, such as myoma and adenomyosis. We herein report a 47-year-old Japanese woman with uterine adenomyosis who developed multiple cerebral infarcts during menstruation. Edoxaban was initially used for prevention but failed to prevent recurrence of thrombosis. However, hysterectomy and bilateral salpingo-oophorectomy resulted in the successful prevention of recurrence of cerebral infarct for five years without antiplatelet or anticoagulant agents. In our patient, the surgical removal of adenomyosis was highly effective for preventing thrombosis in a patient with adenomyosis.

BACKGROUND 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

Introduction 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. Methods and results EMIT-AF/VTE collected data of patients from Europe, Korea, and Taiwan. Timing and duration of peri-procedural interruption of edoxaban were at the treating physician's discretion. Pacemakers or monitoring devices were implanted into 136 patients who were evaluated from five 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 DOAC 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 three days after the procedure. Conclusion/relevance 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. This article is protected by copyright. All rights reserved.

BACKGROUND The role of direct oral anticoagulants as compared with vitamin K antagonists for atrial fibrillation after successful transcatheter aortic-valve replacement (TAVR) has not been well studied. METHODS We conducted a multicenter, prospective, randomized, open-label, adjudicator-masked trial comparing edoxaban with vitamin K antagonists in patients with prevalent or incident atrial fibrillation as the indication for oral anticoagulation after successful TAVR. The primary efficacy outcome was a composite of adverse events consisting of death from any cause, myocardial infarction, ischemic stroke, systemic thromboembolism, valve thrombosis, or major bleeding. The primary safety outcome was major bleeding. On the basis of a hierarchical testing plan, the primary efficacy and safety outcomes were tested sequentially for noninferiority, with noninferiority of edoxaban established if the upper boundary of the 95% confidence interval for the hazard ratio did not exceed 1.38. Superiority testing of edoxaban for efficacy would follow if noninferiority and superiority were established for major bleeding. RESULTS A total of 1426 patients were enrolled (713 in each group). The mean age of the patients was 82.1 years, and 47.5% of the patients were women. Almost all the patients had atrial fibrillation before TAVR. The rate of the composite primary efficacy outcome was 17.3 per 100 person-years in the edoxaban group and 16.5 per 100 person-years in the vitamin K antagonist group (hazard ratio, 1.05; 95% confidence interval [CI], 0.85 to 1.31; P���=���0.01 for noninferiority). Rates of major bleeding were 9.7 per 100 person-years and 7.0 per 100 person-years, respectively (hazard ratio, 1.40; 95% CI, 1.03 to 1.91; P���=���0.93 for noninferiority); the difference between groups was mainly due to more gastrointestinal bleeding with edoxaban. Rates of death from any cause or stroke were 10.0 per 100 person-years in the edoxaban group and 11.7 per 100 person-years in the vitamin K antagonist group (hazard ratio, 0.85; 95% CI, 0.66 to 1.11). CONCLUSIONS In patients with mainly prevalent atrial fibrillation who underwent successful TAVR, edoxaban was noninferior to vitamin K antagonists as determined by a hazard ratio margin of 38% for a composite primary outcome of adverse clinical events. The incidence of major bleeding was higher with edoxaban than with vitamin K antagonists. (Funded by Daiichi Sankyo; ENVISAGE-TAVI AF ClinicalTrials.gov number, NCT02943785.).

BACKGROUND AND OBJECTIVE Atrial fibrillation and anticoagulation decrease the quality of life of patients. The aim of this study is to assess the quality of life and the degree of satisfaction after changing from VKA to edoxaban anticoagulants. MATERIAL AND METHODS Prospective, multicentre study, including 105 patients in dicumarinic anticoagulant treatment replaced by edoxaban. Their quality of life was evaluated before and after using the EQ-5D questionnaire, and the degree of satisfaction with CRES-4 scale. RESULTS Average 75 years, CHA2DS2VASC3,5 and HASBLED2,1; thromboembolic events and clinically relevant bleeding during follow-up

Few data are available regarding the prevalence of left atrium (LA) thrombi in atrial fibrillation (AF) patients treated with non-vitamin K antagonist oral anticoagulants (NOACs). Methods: We evaluated the prevalence and predictors of LA/LA appendage (LAA) thrombi in non-valvular AF patients treated with NOACs referring to a single centre for a scheduled electrical cardioversion (ECV) or catheter ablation (CA). Transesophageal echocardiography (TEE) was performed within 12 h prior to the index procedure. A total of 352 consecutive patients with non-valvular AF treated with NOACs were included in this analysis (ECV group n = 176 and CA group n = 176) between 2013 and 2018. 85 patients (24.2%) were on dabigatran, 150 (42.7%) on rivaroxaban, 104 (29.6%) on apixaban and 13 (3.7%) on edoxaban. A LA/LAA thrombus was detected by TEE in 27 (7.7%) patients, 18 in the ECV group and nine in the ablation group; 18 (5.1%) patients presented dense LA/LAA spontaneous echo contrast (SEC). Predictors of LA/LAA thrombi were a CHA2DS2-VASc score > 3 (OR 4.54, 95% CI 1.50 − 13.70, p value = .007) and obesity (OR 6.01, 95% CI 1.95 − 18.50, p value = .001). Among real-world patients with non-valvular AF treated with NOACs, we found a high incidence of LA/LAA thrombi compared to previous reports. The main predictors of LA/LAA thrombosis were a CHA2DS2-VASc score > 3 and obesity.

Since direct oral anticoagulants (DOAC) are administered frequently to an elderly, co-morbid population, medical emergencies including trauma, acute bleeding or organ failure are not uncommon. In these situations, the type, dosage or the time of last intake of anticoagulants is often unknown and single substance analysis by functional tests is only possible if the substance contained in the sample is known. A reliable and validated toxicology screen of DOAC and argatroban would be helpful inform not only attending physicians in the emergency department but also law enforcement and courts of justice. After precipitation with acetone, HPLC separation was achieved on a Phenomenex Luna Pentafluorophenyl Colum using acetonitrile–water (90:10, v/v) as mobile phase system. Detection was performed using a 3200 Q Trap mass spectrometer (AB Sciex). For analysis MRM Scans (MS/MS) with positive ionization were chosen. The method was validated for blank serum as the matrix of choice. Limits of detection are between 0.5 and 1.0 ng/mL, limits of quantification are between 1.9 and 3.6 ng/mL and recoveries are above 60%. The applicability of the method was demonstrated by the determination of DOAC in body fluids from forensic cases and in therapeutic drug monitoring. The rapid simultaneous detection and quantification of apixaban, argatroban, dabigatran etexilate, dabigatran, edoxaban and rivaroxaban in body fluids by HPLC–MS/MS closes an important gap in emergency toxicology.

Background: The ELDERCARE-AF trial demonstrated that low-dose edoxaban prevented stroke or systemic embolism (SE) in very elderly Japanese patients with non-valvular atrial fibrillation (NVAF) in whom standard oral anticoagulant therapy was inappropriate because of high bleeding risk. The aim of this study was to elucidate the characteristics and outcomes of such patients in routine clinical practice. Methods and Results: Data were extracted from the Fushimi AF Registry for ELDERCARE-eligible NVAF patients aged ≥80 years, with a CHADS2 score ≥2 and ≥1 bleeding risk factors, as shown in the ELDERCARE-AF trial. ELDERCARE-eligible patients (n=549; 12.8% of the entire cohort, 52.9% of those aged ≥80 years and with CHADS2 score ≥2) were less often male, were older, had more comorbidity and higher risk scores than non-eligible patients from the entire cohort (n=3,734). The crude incidence (% per patient-year) of adverse events was significantly higher in ELDERCARE-eligible than non-eligible patients (stroke/SE, 4.8% vs. 2.0%; major bleeding, 3.6% vs. 1.9%; all-cause mortality, 15.5% vs. 3.9%; cardiovascular death, 2.7% vs. 0.6%; all log-rank P

Oral anticoagulant therapy is widely used in different patients for the prevention and treatment of thromboembolic events: in atrial fibrillation, deep vein thrombosis/pulmonary embolism, acute coronary syndrome, in the early postoperative period after orthopedic surgery. Nowadays it is possible to use vitamin K antagonists (warfarin) as well as direct oral anticoagulants (DOAC): dabigatran, rivaroxaban, apixaban and edoxaban. The mai complication of any anticoagulant therapy is bleeding (gastrointestinal, intracranial, etc.), which seriously limits its usage. In this review the incidence of gastrointestinal bleeding (GIB) associated with oral anticoagulants intake was analyzed according to the results of both large randomized and postregistration trials. Furthermore, the effect of age on the risk of GIB development is discussed, and also aspects of the pathophysiology of gastrointestinal mucosa lesions in patients taking DOAC are considered.

Thrombotic complications are common in patients with severe COVID-19 pneumonia with important consequences on the diagnostic and therapeutic management. We report a consecutive series of five patients on long-term oral anticoagulation therapy who presented to our hospital for severe COVID-19 pneumonia associated with segmental acute pulmonary embolism despite adherence to therapy and with an adequate anticoagulant range at the time of the event. Four patients were receiving a direct oral anticoagulant (two with edoxaban, one with rivaroxaban and one with apixaban) and one patient a vitamin K antagonist. No significant thrombotic risk factors, active cancer, or detectable venous thromboembolism were present. In all cases, elevated d-dimer and fibrinogen levels with a parallel rise in markers of inflammation were documented. The combination of these findings seems to support the hypothesis that considers the local vascular damage determined by severe viral infection as the main trigger of thrombi detected in the lungs, rather than emboli from peripheral veins.

The article presents updated information on the frequency of use of non-recommended low dosing of direct oral anticoagulants (dabigatran, rivaroxaban, apixaban and edoxaban). It gives substantiation of the urgency of the issue of providing the maximum efficiency of the use of anticoagulants in clinical practice, taking into account the high prevalence of atrial fibrillation and the pharmacological characteristics of the most commonly used drugs. The effects of such an unreasonable reduction in anticoagulant doses in elderly and senile patients are discussed. The results of recent observational studies that assessed the relationship between the use of direct oral anticoagulants and the risk of adverse clinical outcomes are presented. The data on the relationship between the use of unreasonably low dosing of anticoagulants in patients with atrial fibrillation, which were recently obtained during the implementation of the GARFIELD-AF registry, are discussed. The data on a rather high variability of concentrations of direct oral anticoagulants are presented. The frequency of using apixaban in an unreasonably reduced dose, as well as the effects of using non-recommended doses of apixaban hold a specific place in the article. The unreasonableness of attempts to further reduce the risk of bleeding due to unreasonable reduction of apixaban dosing is emphasized, taking into account the stable data on the high safety of recommended dosing of apixaban, as well as the possible decrease in the effect if the dose reduction is not recommended. The data on the criteria for dose reduction, which are adopted in different countries, are presented. The proposed terms to designate different doses of direct oral anticoagulants, depending on their study in the course of large, randomized trials are discussed.

Background and Purpose: Data on clinical outcomes for nonvitamin K antagonist oral anticoagulant (NOACs) and warfarin in patients with atrial fibrillation and cancer are limited, and patients with active cancer were excluded from randomized trials. We investigated the effectiveness and safety for NOACs versus warfarin among patients with atrial fibrillation with cancer. Methods: In this nationwide retrospective cohort study from Taiwan National Health Insurance Research Database, we identified a total of 6274 and 1681 consecutive patients with atrial fibrillation with cancer taking NOACs and warfarin from June 1, 2012, to December 31, 2017, respectively. Propensity score stabilized weighting was used to balance covariates across study groups. Results: There were 1031, 1758, 411, and 3074 patients treated with apixaban, dabigatran, edoxaban, and rivaroxaban, respectively. After propensity score stabilized weighting, NOAC was associated with a lower risk of major adverse cardiovascular events (hazard ratio, 0.63 [95% CI, 0.50–0.80]; P =0.0001), major adverse limb events (hazard ratio, 0.41 [95% CI, 0.24–0.70]; P =0.0010), venous thrombosis (hazard ratio, 0.37 [95% CI, 0.23–0.61]; P P =0.0171) compared with warfarin. The outcomes were consistent with either direct thrombin inhibitor (dabigatran) or factor Xa inhibitor (apixaban, edoxaban, and rivaroxaban) use, among patients with stroke history, and among patients with different type of cancer and local, regional, or metastatic stage of cancer ( P interaction >0.05). When compared with warfarin, NOAC was associated with lower risk of major adverse cardiovascular event, and venous thrombosis in patients aged P interaction Conclusions: Thromboprophylaxis with NOACs rather than warfarin should be considered for the majority of the atrial fibrillation population with cancer.

Objectives Monitoring is essential to safe anticoagulation prescribing and requires close collaboration among pathologists, clinicians, and pharmacists. Methods We describe our experience in the evolving strategy for laboratory testing of unfractionated heparin (UFH). Results An intrainstitutional investigation revealed significant discordance between activated partial thromboplastin time (aPTT) and antifactor Xa (anti-Xa) assays, prompting a transition from the former to the latter in 2013. With the increasing use of oral factor Xa inhibitors (eg, apixaban, rivaroxaban, edoxaban, betrixaban), which interfere with the anti-Xa assay, we adapted our protocol again to incorporate aPTT in patients admitted on oral Xa inhibitors who require transition to UFH. Conclusions Our experience demonstrates key challenges in anticoagulation and highlights the importance of clinical pathologists in helping health systems adapt to the changing anticoagulation landscape.

Introduction: Direct oral anticoagulants (DOACs) changed the landscape of atrial fibrillation (AF) treatment, but also brought with them new challenges in terms of accessibility and compliance. The purpose of this study was to assess adherence to DOACs, and its determinants in a population of AF patients. Methods: Single-center retrospective study including all patients with non-valvular AF treated with a DOAC from the outpatient general cardiology list at a tertiary center, whose first DOAC prescription was between 1 April 2016 and August 2018. The number of pharmacy refills from the day of first prescription to 31 August 2018 was counted (by means of an electronic prescription platform). Medication refill adherence (MRA) was calculated by dividing the total days' supply by the number of days under therapy. Non-compliance was defined as MRA

Background & Aims While direct oral anticoagulants (DOACs) are increasingly used in patients with liver disease, safety data especially in advanced chronic liver disease (ACLD) are limited. Methods Liver disease patients receiving DOAC treatment (ACLD: n = 104; vascular liver disease: n = 29) or vitamin K antagonists (VKA)/low-molecular-weight heparin (LMWH; ACLD: n = 45; vascular: n = 13) between January 2010 and September 2020 were retrospectively included. Invasive procedures and bleeding events were recorded. Calibrated anti-Xa peak levels and thrombomodulin-modified thrombin generation assays (TM-TGAs) were measured in a subgroup of 35/28 DOAC patients. Results Among patients receiving DOAC, 55 (41.3%) had advanced liver dysfunction (Child-Pugh-stage [CPS] B/C) and 66 (49.6%) had experienced decompensation. Overall, 205 procedures were performed in 60 patients and procedure-related bleedings occurred in 7 (11.7%) patients. Additionally, 38 (28.6%) patients experienced spontaneous (15 minor, 23 major) bleedings during a median follow-up of 10.5 (IQR: 4.0-27.8) months. Spontaneous bleedings in ACLD patients were more common in CPS-B/C (at 12 months: 36.9% vs CPS-A: 15.9%, subdistribution hazard ratio [SHR]: 3.23 [95% CI: 1.59-6.58], P < .001), as were major bleedings (at 12 months: 22.0% vs 5.0%, SHR: 5.82 [95% CI: 2.00-16.90], P < .001). Importantly, CPS (adjusted SHR: 4.12 [91% CI: 1.82-9.37], P < .001), but not the presence of hepatocellular carcinoma or varices, was independently associated with major bleeding during DOAC treatment. Additionally, ACLD patients experiencing bleeding had worse overall survival (at 12 months: 88.9% vs 95.0% without bleeding; P < .001). Edoxaban anti-Xa peak levels were higher in patients with CPS-B/C (345 [95% CI: 169-395] vs CPS-A: 137 [95% CI: 96-248] ng/mL, P = .048) and were associated with lower TM-TGA. Importantly, spontaneous bleeding rates were comparable to VKA/LMWH patients. Conclusions Anticoagulants including DOACs should be used with caution in patients with advanced liver disease due to a significant rate of spontaneous bleeding events.

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.

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

Purpose: We aimed to investigate the clinical performance of edoxaban for the treatment of pulmonary embolism (PE) in hospitalized COVID-19 patients. Methods: We conducted a retrospective analysis selecting hospitalized patients with COVID-19 admitted to our Institution from 20 May 2020 to 20 November 2020 with computer tomography (CT) detected PE at admission, treated with edoxaban after initial parenteral therapy. Clinical outcomes were compared between patients with and without ARDS at admission and between those with and without CT confirmed PE resolution. Results: 50 patients were included. Mean follow-up was 42.5±10days. No baseline differences were found between patients with ARDS (30%) and those without ARDS at admission. Patients with PE resolution (84%) were younger (P =0.03), had a shorter duration of fondaparinux therapy (9.9±3.8 vs 15.8±7.5days; P =0.0015) and length of hospitalization (36±8 vs 46±9days: P =0.0023) compared with those without PE resolution. 2 patients experienced major bleedings. At multivariate analysis the time to edoxaban switch was the only predictor of the PE resolution (HR: 0.92; 95% C.I. 0.86 to 0.99). Conclusion: Edoxaban was an effective and safe treatment for acute PE in COVID-19 setting.

Standard therapy for venous thromboembolism (VTE) includes the use of heparins and vitamin K antagonists. Randomized clinical trials have shown that non-vitamin K oral anticoagulants are as effective and safe as standard therapy in VTE treatment, with an improved pharmacological profile. Edoxaban, a direct inhibitor of factor Xa, has demonstrated noninferiority to standard therapy for the treatment of VTE, preserving a high safety profile even in long-term therapy, in frail patients and in severe clinical presentations. The present paper focuses on the role of edoxaban in VTE treatment, from general population to cancer patients, presenting the available data from randomized clinical trials and real world, to discuss edoxaban use in clinical practice.Lay abstractAnticoagulants are the main treatment for venous thromboembolism (VTE), a condition in which a blood clot forms in the deep veins of the body, in areas such as the leg. Currently, direct oral anticoagulants are available as an alternative to warfarin, a drug that is sensitive to changes in the diet and requires constant monitoring. Direct-oral anticoagulants have been shown in large-scale studies to be as effective and safe as warfarin in the treatment of this disease, with the advantage of not being affected by the food the patient eats. Among these, edoxaban only needs to be taken once a day and has obtained many favorable results in high-risk populations (such as the elderly, patients with cancer, those receiving prolonged treatment or those with severe VTE). In this review we discuss the role of edoxaban for the treatment of VTE in several scenarios and review its role in clinical practice.Tweetable abstractEdoxaban is effective and safe for the treatment of venous thromboembolism (VTE) even in special population. Caution is needed in some patients to avoid major bleeding events. Favorable results are also shown in the ETNA VTE study, a real-world data prospective registry. #edoxaban #VTE #efficacy #safety

Background Lupus anticoagulant (LA)-detection in anticoagulated patients is an unmet need, which becomes even more cogent with the introduction of direct oral anticoagulants (DOAC) that may lead to false-positive results. Aims We aimed to investigate the effect of a commercially available DOAC absorbent on residual drug concentrations, and on integrated procedures for LA-detection. Methods Blood from patients treated for atrial fibrillation with either dabigatran (n = 39), rivaroxaban (n = 55), apixaban (n = 47) or edoxaban (n = 47) were collected at peak and trough, and centralized for testing with two LA integrated procedures [i.e., the silica clotting time (SCT) and dilute Russel viper venom (dRVVT)] before and after DOAC absorbent exposure. Results The commercially available DOAC absorbent investigated in this study proved effective in reducing the concentrations of all the investigated DOAC, although small residual drug was detected after absorption, especially in patients on edoxaban. Results mimicking LA were observed in patients on DOAC before absorbent exposure, especially for rivaroxaban when testing was performed with dRVVT (88% rate at peak and 20% at trough) and much less with SCT (12% at peak and 8% at trough). The correspondent rate of results mimicking LA in patients on rivaroxaban after exposure was reduced [dRVVT (peak 8%, trough 4%); SCT (peak and trough 8%)], but not abolished. Conclusions Overall, in vitro DOAC absorbance by active charcoal compounds is a useful laboratory tool for LA-detection in patients on DOAC. Caution should however be exerted when used in daily practice.

Taru Hallinen,1 Erkki Soini,1 Christian Asseburg,1 Miika Linna,2 Pia Eloranta,3 Sari Sintonen,3 Mikko Kosunen3 1ESiOR Oy, Kuopio, Finland; 2Aalto University, Department of Industrial Engineering and Management, Espoo, Finland; 3Pfizer Oy, Helsinki, FinlandCorrespondence: Taru Hallinen ESiOR Oy, Tulliportinkatu 2 LT4, Kuopio, FI-70100, FinlandTel +358 50 568 1894Email taru.hallinen@esior.fiPurpose: Direct oral anticoagulant (DOAC) use for the prevention of thromboembolic complications in patients with non-valvular atrial fibrillation (AF) has increased steadily in Finland. DOACs have been shown to be cost-effective in comparison to warfarin, but published evidence of relative cost-effectiveness between DOACs is still scarce and mostly based on indirect comparisons of clinical trial evidence. The aim of this study was to compare the cost-effectiveness of apixaban to dabigatran, rivaroxaban and warfarin in a Finnish setting using real-life evidence where available.Patients and Methods: A lifetime Markov simulation model used previously in a published Finnish assessment comparing apixaban and warfarin was modified and updated with the relative effectiveness and safety data available from the real-world NAXOS-study and representative Finnish input data for patient characteristics, event risks, mortality, resource use, costs, and quality of life. Apixaban’s cost-effectiveness was assessed from health care payer perspective (using 3% per year discount rate) based on incremental cost-effectiveness ratio (ICER, cost per quality-adjusted life year [QALY] gained), probability of cost-effectiveness (at willingness-to-pay [WTP] of 35,000 euros/QALY), and net monetary benefit (NMB).Results: Apixaban increased the average modelled quality-adjusted life-expectancy and reduced the average total health care costs of AF patients when compared to warfarin (+0.14 QALYs, − 3691 euros), dabigatran (+0.11 QALYs, − 404 euros), and rivaroxaban (+0.03 QALYs, − 43 euros). The resulting NMB of apixaban versus warfarin, dabigatran and rivaroxaban was 8723, 4168, and 1129 euros, respectively. The respective probabilities of apixaban being cost-effective against each comparator were 100%, 92.7%, and 64.0%.Conclusion: In this modelling study, apixaban dominated other anticoagulants in the Finnish real-life setting.Keywords: apixaban, cost-utility, dabigatran, economic evaluation, rivaroxaban, warfarin

Cerebral venous thrombosis (CVT) is caused by partial or complete occlusion of the major cerebral venous sinuses or the smaller feeding cortical veins which predispose to the risk of venous infarction and hemorrhage. Current guidelines recommend treating CVT with either low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) followed by an oral vitamin K antagonist (VKA) for 3-12 months. Direct oral anticoagulants (DOACs) have already established benefit over warfarin as a long-term treatment of symptomatic venous thromboembolic disorder like deep vein thrombosis (DVT), and pulmonary embolism (PE) given its equal efficacy and better safety profile. The benefit of DOACs over warfarin as a long-term anticoagulation for CVT has likewise been extensively studied, yet it has not been approved as first-line therapy in the current practice. We therefore performed a systematic review and meta-analysis of relevant studies to generate robust evidence regarding the safety and efficacy of DOACs in CVT. This meta-analysis demonstrates that the use of DOACs in CVT has similar efficacy and safety compared to VKAs with better recanalization rate.

Background Factor Xa inhibitors (FXaIs) are increasingly used without having sufficient drug–drug interaction data. Using a microdosed cocktail methodology could support filling the knowledge gap quickly. Methods In a randomised crossover trial, we investigated the drug–drug interactions between six oral azole antifungals and a microdosed FXaI cocktail containing 25 µg rivaroxaban, 25 µg apixaban, and 50 µg edoxaban. Additionally, different enzyme activities were also monitored using a microdosed cocktail approach. The six different azole antifungals were administered in therapeutic doses over a 24 h period, while the microdosed cocktails were administered 1 h after administration of the azole antifungals. Results Ketoconazole and posaconazole were the strongest perpetrators, showing similar increases as apixaban (area under the concentration–time curve ratio [AUCR] 1.64 and 1.62, respectively) and edoxaban (AUCR 2.08 and 2.1, respectively), whereas ketoconazole increased rivaroxaban 2.32-fold but only increased posaconazole 1.37-fold. All other azole antifungals showed less perpetrator effects on the FXaIs. Cytochrome P450 (CYP) 3A inhibition was confirmed using microdosed midazolam, with ketoconazole also the most potent perpetrator (8.42-fold). Conclusion Drug–drug interactions for three victim drugs of the same drug class (FXaIs) with different clearance mechanisms can be studied using a microdosed cocktail approach. Using members of the azole antifungal drug class as perpetrators, multiple interactions can be studied in one trial, and a more detailed insight into the underlying interaction mechanisms is possible. Clinical Trial Registration EudraCT number: 2017-004453-16. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-021-01051-9.

Background Non-vitamin K antagonist oral anticoagulants (NOACs) are as effective and safe as warfarin for thromboembolic prevention and treatment. The efficacy of NOACs lacks evidence from large and randomized studies in patients with inherited severe thrombophilia, including protein S deficiency. Further, some concerns still exist regarding the relative efficacy of edoxaban in preventing arterial thromboembolism in patients with normal to high creatinine clearance (CrCl). We present a case of a rare complication of lead thrombus under standard-dose edoxaban in a patient with protein S deficiency and supernormal renal function. Case presentation A 65-year-old man experienced persistent chest tightness and a high level of D-dimer. Chest computed tomography (CT) showed a lead thrombus at the superior vena cava. He had a medical history including, paroxysmal atrial fibrillation (PAf), sick sinus syndrome after permanent pacemaker implantation, and transient ischemic attack. He received standard-dose edoxaban (60 mg daily) after PAf was diagnosed. His estimated CrCl was 98.6–102.1 mL/min. However, protein S deficiency (22.8%; normal range: 55–130%) was diagnosed. After switching to dabigatran (150 mg twice daily) for 3 months, the chest CT showed lead thrombus resolution and no symptoms were seen during the follow-up period. Conclusions This case was a rare complication of lead thrombus in a protein S deficient patient with normal renal function receiving standard-dose edoxaban. Edoxaban efficacy is uncertain in patients with protein S deficiency, and intracardiac devices also increase the risk of thromboembolic events.

Background The antithrombotic effect of direct oral anticoagulants (DOAC) in specific clinical scenarios is difficult to assess. Objective This study aimed to evaluate the effect of DOAC on thrombin generation (TG) in relation to their plasma level. Methods Eighty patients newly started on anticoagulation were included, 20 patients for each DOAC-apixaban, edoxaban, rivaroxaban, and dabigatran. Plasma was sampled before DOAC (baseline), at plasma peak time, 6 and 12 hours after starting DOAC for quantification of drug levels and TG. Results The baseline TG before DOAC intake showed inter-individual variability. All DOACs significantly prolonged lag time (LT) and time to peak (TTP), but did not change endogenous thrombin potential (ETP). Anti-Xa inhibitors but not dabigatran reduced thrombin peak, but the effect of apixaban at plasma peak was less pronounced (factor 1.6). LT and TTP prolongation of dabigatran was lower compared to anti-Xa inhibitors. All DOACs showed a nonlinear dose-response relationship, with the greatest antithrombotic effect at lower DOAC plasma levels. The inhibition of TG parameters between baseline and peak was parallel between individual patients but the coefficient of variation of TG was lower compared to drug levels. Conclusion The antithrombotic effect at DOAC peak plasma level measured by TG depends on the patient-specific baseline TG level and the drug-specific inhibition by the particular DOAC. Although peak plasma levels have a high variability, the variation of TG is lower compared to drug levels. Therefore, TG assays may be superior to plasma levels in the assessment of the intensity of anticoagulation.

Purpose Cardiac surgery patients frequently require anticoagulation. Warfarin remains the preferred agent, and a few trials have reported negative outcomes with the use of direct-acting oral anticoagulants (DOACs) in these patients. Therefore, limited literature exists that supports the dosing, safety, and efficacy of DOACs within the cardiac surgery population. Methods This single-center, retrospective analysis was conducted at a tertiary academic medical center. All data were extrapolated from electronic medical records of qualifying patients from August 2017 to August 2019. Adult patients were included if they received at least 1 of 4 DOACs (apixaban, rivaroxaban, edoxaban, or dabigatran) after undergoing one of the following cardiac surgeries: coronary artery bypass graft, bioprosthetic valve replacement, aortic surgery, or valve repair. The composite safety end point included major bleeding and clinically relevant nonmajor bleeding, as defined by the International Society on Thrombosis and Hemostasis. The composite efficacy outcome of thromboembolic events included deep vein thrombosis, pulmonary embolism, ischemic stroke, and intracardiac thrombus. Findings A total of 305 patient charts were identified for analysis; 229 patients met the inclusion criteria. The composite safety outcome occurred in 12 patients (5.2%) within 90 days after cardiac surgery. One patient (0.4%) experienced a thromboembolic event within 90 days after cardiac surgery. The most commonly prescribed DOAC was apixaban (79.0%). US Food and Drug Administration–approved dosing was used in 91.3% of patients, and DOACs were primarily used for the indication of stroke prevention in atrial fibrillation or atrial flutter (88.2%). Implications These data provide insight into the prescribing practices, efficacy, and safety of DOACs in cardiac surgery patients.

Background Although direct oral anticoagulants (DOACs) have been shown to be effective at reducing the risk of stroke in patients with atrial fibrillation/flutter (AF), they are sometimes underdosed off-label to mitigate their associated higher bleeding risk. We sought to evaluate frequency and clinical outcomes of inappropriate underdosing of DOACS in patients with AF. Methods We conducted a study of subjects with AF who had a clinical indication for stroke prophylaxis (with a congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischemic attack, vascular disease, age 65 to 47 years, sex category [CHA2DS2-VASc] of 2 or greater) and were prescribed 1 of the 4 clinically approved DOACs (apixaban, rivaroxaban, dabigatran, or edoxaban). We compared all-cause mortality, composite of stroke and systemic embolism, composite of myocardial infarction (MI), acute coronary syndromes (ACS), and coronary revascularization, and major bleeding between patients appropriately dosed and inappropriately underdosed. Results A total of 8125 patients met inclusion criteria, with a mean follow up of 2.2 ± 2 years. Of those, 1724 patients (21.2%) were inappropriately dosed. After adjusting for baseline variables, there was no difference in all-cause mortality, risk of stroke or systemic embolism, International Society on Thrombosis and Haemostasis (ISTH) major bleeding, or composite of myocardial infarction, acute coronary syndromes, or coronary revascularization between patients appropriately dosed and inappropriately underdosed. In subgroup analysis, only apixaban demonstrated an increased incidence all-cause mortality (hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.03-1.49) with inappropriate underdosing. There was no difference in the remaining clinical outcomes noted on subgroup analysis. Conclusion Underdosing of DOACs did not minimize risk of bleeding, systemic embolization or all-cause mortality in patients with AF. Inappropriate underdosing with apixaban in particular was associated with increased all-cause mortality.

Background There are limited studies comparing the risk of osteoporosis and fractures between different direct oral anticoagulants (DOACs) and vitamin K antagonists (VKA) in non-valvular atrial fibrillation (AF). Using a network meta-analysis (NMA), we compared osteoporotic fractures among 5 different treatment arms, viz. dabigatran, rivaroxaban, apixaban, edoxaban, and VKA. Methods Ten studies, including 5 randomized control trials and 5 population-based studies, with a total of 321,844 patients (148,751 and 173,093 in the VKA and DOAC group, respectively) with a median follow-up of 2 years, were included. A Bayesian random-effects NMA model comparing fractures among the treatment arms was performed using MetInsight V3. Sensitivity analysis excluded studies with the highest residual deviances from the NMA model. Results The mean age of the patients was 70 years. The meta-analysis favored DOACs over VKA with significantly lower osteoporotic fracture (odds ratio [OR], 0.77; 95% credible interval [CrI], 0.70-0.86). The NMA demonstrated that fractures were significantly lower with apixaban compared with dabigatran (OR, 0.64; 95% CrI, 0.44-0.95); however, fractures were statistically similar between apixaban and rivaroxaban (OR, 0.84; 95% CrI, 0.58-1.24) and dabigatran and rivaroxaban (OR, 1.32; 95% CrI, 0.90-1.87). Based on the Bayesian model of NMA, the probability of osteoporotic fracture was highest with VKA and lowest with apixaban, followed by rivaroxaban, edoxaban, and dabigatran. Conclusions The decision to prescribe anticoagulants in elderly patients with AF should be made not only based on thrombotic and bleeding risks but also on the risk of osteoporotic fracture; these factors should be considered and incorporated in contemporary cardiology practice.

Purpose The main purpose of prescribing oral anticoagulants in patients undergoing total knee and total hip replacement surgery is to prevent venous thromboembolism (VTE). The present study aimed to summarize evidence from economic evaluations regarding new oral anticoagulants (NOACs) used in VTE prophylaxis after joint replacement surgery. Methods To obtain relevant literature on economic evaluations of NOACs used in the prevention of VTE following joint replacement surgery, we searched the Cochrane Library, PubMed, Web of Science, Embase, and Scopus, as well as specialized economic evaluation databases, for articles published from January 2008 to December 2019. Next, 2 reviewers screened the titles and abstracts of studies, extracted data from the full-text articles, and assessed the quality of the methodologies using the Quality of Health Economic Studies checklist. Findings Twenty-eight studies of economic evaluations met the inclusion criteria of the research. The quality assessment showed that 20 articles had scores within the range of 75 to 100 (high quality), and 9 studies had scores within the range of 50 to 74 (moderate quality). All of the identified studies had been carried out based on modelling, and 23 studies used decision trees to model acute events after surgery. In addition, 20 studies utilized a Markov model to capture long-term complications of VTE. The results showed that rivaroxaban was more cost-effective than apixaban and dabigatran from a perspective of the health care system in the prevention of VTE after total knee and total hip replacement surgery. In addition, apixaban was associated with a lower risk for bleeding events than other NOACs, making it the most cost-effective NOAC from the perspective of the payer. Implications The results suggest that NOACs are cost-effective alternatives to low-molecular-weight heparins. Rivaroxaban and dabigatran were assessed as the most and least cost-effective prophylaxis options, respectively, after joint replacement surgery for the prevention of VTE. It is recommended that future research be conducted on economic evaluations of edoxaban.

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

Direct oral anticoagulants (DOACs) are increasingly preferred anticoagulation options, with a lower risk of intracranial haemorrhage versus warfarin. Bleeding is, however, a predictable adverse event requiring urgent management. Specific DOAC reversal agents may be available, such as idarucizumab for the thrombin inhibitor dabigatran, and andexanet alfa for the factor Xa inhibitors apixaban, edoxaban (off-label) and rivaroxaban; but prothrombin complex concentrates are still often used in addition to supportive measures and haemostatic support.

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

Oral anticoagulants (OAC) have shown to affect bone mineral density and cause osteoporosis. Limited studies have investigated the relationship between its use and risk of osteoporosis. We aim to compare the risk of osteoporosis in patients on warfarin versus direct oral anticoagulants (DOACs).A retrospective single-center cohort study was conducted in veterans age 18 years of age in whom warfarin or DOACs were newly initiated between January 1st, 2012 to April 1st, 2020 at Salem VA Medical Center. Patients on OAC for at least 90 days qualified for inclusion and excluded if they were pregnant or had history of mechanical valve and mitral stenosis, on edoxaban or had previous history of osteoporosis or use of antiosteoporosis medication. Primary outcome was comparing incidence of new-onset osteoporosis between warfarin and DOACs. Secondary outcomes included comparing incidence of all clinical fractures, hip fractures, major bleeding and intracranial bleed between the treatments. Cox proportional hazard ratios (HRs) and 95% confidence intervals (CI) comparing the two treatment groups were calculated.A total of 1526 patients on DOAC and 1121 in warfarin group were included in the study. After propensity-score (PS) matching, 943 patients were included in each arm. Baseline characteristics were similar after PS-matching. DOAC treatment was associated with lower incidence of new-onset osteoporosis as compared to warfarin in matched cohort (aHR: 0.19, 95% CI: 0.10-0.36; p 0.0001). The risk of all clinical fracture and hip fracture was similar in patients receiving DOACs as versus warfarin (aHR: 1.18, 95% CI: 0.82-1.69; p = 0.3671). DOAC use was associated with lower risk of major bleed (aHR: 0.07, 95% CI: 0.03-0.15; p 0.0001) and intracranial bleed (aHR: 0.14, 95% CI: 0.03-0.64; p = 0.0111).Overall, as compared to warfarin, prolonged use of DOACs is associated with lower risk of new-onset osteoporosis. We hope that our study findings will enlighten current clinical practices assuring safe use of OAC in veteran patients.

A significant problem for patients undergoing oral anticoagulation therapy is gastrointestinal bleeding (GIB), a problem that has become increasingly urgent following the introduction of direct oral anticoagulants (DOACs). Furthermore, in recent years a greater focus has been placed on the quality of life (QOL) of patients on long-term oral anticoagulant therapy, which necessitates changes in lifestyle, as well as posing an increased risk of bleeding without producing objective symptomatic relief. Here, we examine current evidence linked to GIB associated with oral anticoagulants, with a focus on randomized control trials, meta-analyses, and postmarketing observational studies. Rivaroxaban and dabigatran (especially the 150-mg bis-in-die dose) appeared to be linked to an increased risk of GIB. The risk of GIB was also greater when edoxaban was used, although this was dependent on the dose. Apixaban did not pose a higher risk of GIB in comparison with warfarin. We provided a summary of current knowledge regarding GIB risk factors for individual anticoagulants, prevention strategies that lower the risk of GIB and management of DOAC therapy after a GIB episode.

Coagulation–fibrinolytic system activity shows daily rhythmicity, with hypercoagulability in the morning and hypocoagulability in the evening. Consequently, the efficacy of anticoagulants may be influenced by their dosing time. Edoxaban, a selective inhibitor of the active form of coagulation factor X (FXa), is taken orally once daily, but the optimal dosing time is unknown. This study evaluated the dosing time-dependent effects of edoxaban on coagulation activity and thrombus formation in rats. Edoxaban (10 mg/kg) or vehicle was administered to Wistar rats at zeitgeber time (ZT)-2 (beginning of the light phase) or ZT14 (beginning of the dark phase), followed by blood collection at ZT4, ZT10, ZT16, or ZT22, to measure the activity of coagulation factors and edoxaban concentrations, or followed by inferior vena cava ligations at ZT4 or ZT16, to assess the efficacy of edoxaban against thrombus formation. Coagulation FX activity was high during the light phase, and a single dose of edoxaban administered at ZT2 inhibited FX activity and thrombus formation more potently compared with the same dose administered at ZT14. The inhibitory effects during the light phase could be attributed, at least in part, to the high blood concentration of edoxaban achieved by dosing at ZT2. Morning dosing of edoxaban leads to a high blood concentration of the drug during the morning hours and thus may better counteract the hypercoagulability and hypofibrinolytic activity characteristic of the morning hours. Optimizing the dosing time may contribute to improving the efficacy of edoxaban.

Purpose: The risk of gastrointestinal bleeding (GIB) can be mitigated by proton pump inhibitor (PPI) co-therapy in patients with atrial fibrillation (AF) treated with anticoagulants. We aimed to evaluate the effect of PPIs on the risk of GIB in Asian patients with AF, treated with oral anticoagulants (OACs), and with a prior history of upper GIB. Methods: Using a nationwide claims database, OAC-naïve patients with AF and a history of upper GIB before initiating OAC treatment between January 2010 and April 2018 were included. Patients were categorized into 10 groups according to the index OAC (warfarin, rivaroxaban, dabigatran, apixaban, and edoxaban) and whether or not they received PPI co-therapy, and were followed up for incidence of major GIB. Results: Among a total of 42,048 patients, 40% were prescribed PPIs as co-therapy with OACs. Over a median 0.6 years (interquartile ranges 0.2–1.7 years) of follow-up, rivaroxaban use without PPIs showed the highest crude incidence of major GIB (2.62 per 100 person-years), followed by the use of warfarin without a PPI (2.20 per 100 person-years). Compared to the patients without PPI use, PPI co-therapy was associated with a significantly lower risk of major GIB, by 40% and 36%, in the rivaroxaban and warfarin groups, respectively. In dabigatran, apixaban, and edoxaban users, PPI co-therapy did not show a significant reduction in the risk of major GIB. Conclusion: Among patients with AF receiving anticoagulant treatment and with a prior history of upper GIB, PPI co-therapy was associated with a significant reduction in the risk of major GIB in patients treated with rivaroxaban and warfarin.

Aspirin and P2Y12 receptor antagonists are widely used across the spectrum of cardiovascular and cerebrovascular diseases. Gastrointestinal complications, including ulcer and bleeding, are relatively common during antiplatelet treatment and, therefore, concomitant proton pump inhibitor (PPI) treatment is often prescribed. However, potential increased risk of cardiovascular events has been suggested for PPIs, and, in recent years, it has been discussed whether these drugs may reduce the cardiovascular protection by aspirin and, even more so, clopidogrel. Indeed, pharmacodynamic and pharmacokinetic studies suggested an interaction through hepatic CYP2C19 between PPIs and clopidogrel, which could translate into clinical inefficacy, leading to higher rates of cardiovascular events. The FDA and the EMA sent a warning in 2010 discouraging the concomitant use of clopidogrel with omeprazole or esomeprazole. In addition, whether the use of PPIs may affect the clinical efficacy of the new P2Y12 receptor antagonists, ticagrelor and prasugrel, remains less known. According to current guidelines, PPIs in combination with antiplatelet treatment are recommended in patients with risk factors for gastrointestinal bleeding, including advanced age, concurrent use of anticoagulants, steroids or non-steroidal anti-inflammatory drugs, and Helicobacter pylori infection. Like vitamin K antagonists (VKAs), DOACs can determine gastrointestinal bleeding. Results from both randomized clinical trials and observational studies suggest that high-dose dabigatran (150 mg bid), rivaroxaban and high-dose edoxaban (60 mg daily) are associated with a higher risk of GI bleeding as compared with apixaban and warfarin. In patients taking oral anticoagulant with GI risk factor, PPI could be recommended, even if usefulness of PPIs in these patients deserves further data. Helicobacter pylori should always be searched, and treated, in patients with history of peptic ulcer disease (with or without complication). Given the large number of patients treated with antithrombotic drugs and PPIs, even a minor reduction of platelet inhibition or anticoagulant effect potentially carries a considerable clinical impact. The present joint statement by ANMCO and AIGO summarizes the current knowledge regarding the widespread use of platelet inhibitors, anticoagulants, and PPIs in combination. Moreover, it outlines evidence supporting or opposing drug interactions between these drugs and discusses consequent clinical implications.

The safety of direct oral anticoagulants (DOACs) in patients after solid organ transplantation (SOT) is not well defined. This study aimed at describing the safety and efficacy of DOACs in patients after SOT. Patients after kidney and/or liver transplantation under maintenance immunosuppression treated with rivaroxaban (n = 26), apixaban (n = 20) and edoxaban (n = 1) were included. Clinical data were collected retrospectively and using a questionnaire. DOAC plasma levels and thrombin generation (TG) were measured in patients after SOT and compared with nontransplanted controls receiving DOACs. DOACs were administered for 84.6 patient-years. Mean immunosuppressive trough levels after DOAC initiation increased from baseline by 18.8 ± 29.6% compared to 3.0 ± 16.5% in matched controls (P = 0.004), without significant differences in dose adjustments. No transplant rejection or significant change in liver or renal function was observed. There was one major bleeding after the observation period but no thromboembolic complication. DOAC plasma levels reached the expected range in all patients. The intrinsic hemostatic activity in transplanted patients was higher compared to nontransplant controls. Treatment with DOACs after SOT is safe and effective. Immunosuppressive trough levels should be monitored after DOAC initiation, particularly in the early phase after SOT. These data should be confirmed in a prospective study.

Objective Direct oral anticoagulants (DOACs) were developed to avoid the limitations of vitamin K antagonists (VKAs). DOACs are associated with a greater incidence of gastrointestinal bleeding and a smaller number of intracranial haemorrhages than VKAs. Therefore, it is important to deepen our knowledge of their safety profiles. The aim of this study was thus to analyse adverse drug reaction (ADR) reports on DOACs and VKAs using the Sicilian Spontaneous Reporting System (SRS) database. Methods All ADR reports with DOACs and VKAs as suspected drugs that were entered into the Sicilian SRS database during the period 2001-2019 were selected. In detail, all reports with the following single active substances were included: dabigatran etexilate, rivaroxaban, apixaban and edoxaban; acenocoumarol and warfarin were included as a comparator group. Descriptive statistical methodology was used to evaluate characteristics of the reported cases with a case-by-case assessment. Results and discussion Out of 521 reports related to anticoagulants, 444 (85.2%) and 77 (14.8%) involved DOACs and VKAs, respectively. DOAC-related reports were mainly of gastrointestinal disorders. In contrast, VKAs were mostly associated with blood and lymphatic system disorders, injury, investigations and vascular disorders. Many more cases of ADRs in the form of gastrointestinal disorders concerned dabigatran etexilate (n = 179, 73.7%) than the other DOACs, while ADRs in the form of blood disorders were mainly associated with acenocoumarol (n = 27, 57.4%). The most commonly reported Preferred Terms for DOACs were dyspepsia (n = 89, 17.1%), upper abdominal pain (n = 41, 9.2%) and pruritus (n = 26, 5.8%), whereas for VKAs, they were anaemia (n = 21, 27.3%) and hypocoagulable state (n = 18, 3.5%). Potentially interacting concomitant medications particularly included antithrombotic agents (n = 19, 4.3%) for DOACs and proton-pump inhibitors (PPIs) (n = 37, 48.1%) and antithrombotic agents (n = 13, 16.9%) for VKAs. Conclusion The ADRs most commonly associated with DOACs, especially dabigatran, were gastrointestinal disorders, particularly gastrointestinal bleeding. Our study also highlights the potential role of drug-drug interactions in the ADRs. The cases of gastrointestinal bleeding highlight the need for careful prescribing of DOACs and use of potentially interacting concomitant drugs.

Introduction Apixaban, a direct factor Xa inhibitor, has been shown to be at least as safe and probably more effective than dalteparin for the treatment of cancer‐associated thrombosis (CAT) as reported in the ADAM‐VTE and Caravaggio studies, which included a low percentage of underweight patients. Lower‐weight–based dosing is supported by cancer‐specific studies such as half‐dose edoxaban in the Hokusai‐VTE cancer trial in individuals weighing 60 kg treated with apixaban 5 mg twice daily, patients weighing ≤60 kg also receiving apixaban 5 mg twice daily, and patients weighing ≤60 kg given half‐dose apixaban (2.5 mg twice daily). Apixaban plasma steady‐state trough levels were determined on a single occasion. Results Mean apixaban plasma trough levels were similar for patients weighing >60 kg on full‐dose apixaban to those weighing ≤60 kg taking 2.5 mg twice daily (mean, 109 ng/dL; 95% confidence interval [CI], 74‐145; standard deviation [SD]: 77.6; and mean,101 ng/dL, 95% CI, 67‐135; SD: 80, respectively). Mean values for low‐weight patients (≤60 kg) on the full 5 mg twice‐daily dosing tended to be higher (mean, 136 ng/dL; 95%CI, 70‐201; SD:114), without statistical significance (P = .22). Conclusions This study supports the rationale for studying weight‐based adjustments in apixaban dosing in prospective studies evaluating safety and efficacy of dose reduction in low‐weight patients with cancer.

Supplemental Digital Content is available in the text., Background: Female sex is an independent risk factor for stroke and systemic embolic events in patients with atrial fibrillation. This study aimed to examine the efficacy and safety profile of edoxaban in women versus men. Methods: The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) randomly assigned 21 105 patients (8040 women) with atrial fibrillation and CHADS2 score ≥2 either to a higher-dose edoxaban regimen, a lower-dose edoxaban regimen, or warfarin. The primary end points of the trial were the composite of stroke or systemic embolic events (efficacy), and International Society on Thrombosis and Haemostasis–defined major bleeding (safety). Results: In comparison with men, women were older, had lower body weight, were more likely to have hypertension and renal dysfunction, but less likely to smoke, drink alcohol, or have diabetes or coronary artery disease. Pretreatment endogenous factor Xa activity was significantly higher in women than in men (92.5% versus 86.1%, P

Infection increases the risk of thrombosis through the activation of inflammation and coagulation. Edoxaban, a direct oral factor Xa inhibitor, is used for the prevention and treatment of thrombotic diseases. The aim of this study was to determine the effects of edoxaban on microvascular thrombus formation in a rat model of lipopolysaccharide (LPS)-induced coagulopathy. Rats were intravenously injected with 7.5 mg/kg of LPS (Escherichia coli 055:B5). Immediately after LPS injection, the rats were treated with subcutaneous injection of edoxaban. At 2 and 6 h after the injection of LPS, biomarkers of coagulation and organ damages and inflammatory cytokines were measured. Microvascular thrombus formation in organs was evaluated using 125I-fibrinogen (human) or by the pathological analysis. Mortality was examined 24 h after LPS injection. After the injection of LPS, D-dimer and thrombin-antithrombin complex increased and platelet numbers decreased, indicating the activation of coagulation. Microvascular thrombi were found in the liver. Markers of liver injury (aspartate aminotransferase and alanine aminotransferase) also increased. Treatment with edoxaban attenuated the changes in the coagulation markers and microvascular thrombus formation in the liver. Edoxaban suppressed the increase in the liver injury markers and reduced the mortality. Edoxaban did not affect the levels of inflammatory cytokines. In conclusions, edoxaban significantly inhibited the activation of coagulation, the formation of microvascular thrombus in the liver and the liver damage, and reduced mortality in rats injected with LPS. These results suggest that the FXa inhibition by edoxaban might be a beneficial therapy for the management of infection-associated thrombosis.

Introduction Although chemoprophylaxis against venous thromboembolism (VTE) after Total Joint Arthroplasty (TJA) is commonly practiced, epidemiology studies have shown Asians have a much lower incidence of VTE. The authors aim to investigate if chemoprophylaxis is really necessary in the Asian population undergoing TJA. Material and methods Literature searched was conducted for randomized controlled trials or quasi-experimental studies investigating efficacy and/or safety of chemoprophylaxis for TJA without language restrictions. Network meta-analysis, comparing the incidence of ‘VTE to be treated’, ‘VTE not to be treated’, ‘Minor bleeding’, and ‘Major bleeding’ amongst the different interventions was performed using multivariate meta-regression model. Results 38 studies (11,769 patients) were included. Total incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) were 14.2% and 0.73% respectively. For outcome on efficiency, edoxaban, low-molecular-weight-heparin (LMWH), fondaparinux, and enoxaparin showed significantly lower Risk Ratio (RR) for ‘VTE to be treated’ compared to Control/Placebo. Although no interventions showed increased incidence of major bleeding, LMWH and fondaparinux showed higher RR for minor bleeding. Enoxaparin displayed the best efficacy and safety profile. Total incidence of symptomatic DVT in studies involving enoxaparin was 1.98% (1.07% in patients who received enoxaparin, 2.92% in Control/Placebo). Total incidence of proximal DVT was 2.93% (2.67% in patients who received enoxaparin, 3.11% in Control/Placebo). Conclusion Asian population has a much lower incidence of VTE events after TJA compared to the Western population. Although Enoxaparin is still efficacious in reducing symptomatic and proximal DVT after TJA, its benefit-to-risk ratio is much lower than described in the Western literature.

Background Cirrhosis-associated portal vein thrombosis (CA-PVT) has been reportedly observed in 5–30% of cirrhotic patients. Moreover, the acute exacerbation of CA-PVT is likely to occur after certain situations, such as a status after abdominal surgery. Safety and efficacy of the direct-acting oral anticoagulant (DOAC) used for cirrhotic patients have been being confirmed. However, use of the DOAC as an initial treatment for CA-PVT appears still challenging especially in the early postoperative period after major surgery in terms of unestablished efficacy and safety in such occasion. Case presentation We herein report a case of the acute exacerbation of CA-PVT in the early postoperative period after abdominal surgery, which was successfully treated with DOAC, edoxaban used as an initial treatment. The patient was a 79-year-old Japanese male with alcoholic cirrhosis. The patient suffered choledocholithiasis and had a mural chronic CA-PVT extending from the superior mesenteric vein to the portal trunk. He underwent open cholecystectomy and choledochotomy. Early postoperative clinical course was uneventful except for abdominal distension due to ascites diagnosed on postoperative day (POD)7 when hospital discharge was planned. Contrast enhancement computed tomography (CE-CT) taken on POD 7 revealed the exacerbation of the CA-PVT. Despite recommendation for extension of hospital admission with low molecular weight heparin treatment, the patient strongly hoped to be discharged. Unwillingly, we selected DOAC, edoxaban, as an initial treatment, which was commenced the day after discharge (POD8). As a result, the remarkable improvement of the exacerbated CA-PVT was confirmed by the CE-CT taken on POD21. Any bleeding complications were not observed. Although a slight residue of the CA-PVT remains, the patient is currently doing well 4 years after surgery and is still receiving edoxaban. Any adverse effects of edoxaban have not been observed for 4 years. Conclusions A case of successful treatment of the acute exacerbation of CA-PVT with edoxaban was reported. Moreover, edoxaban has been safely administered in a cirrhotic patient for 4 years. The findings obtained from the present case suggest that DOAC can be used as an initial treatment for CA-PVT even in early postoperative period after major abdominal surgery.

Edoxaban, a factor Xa inhibitor, is a direct oral anticoagulant (DOAC). DOACs may have a lower incidence of drug-drug interactions (DDIs) than vitamin K antagonists such as warfarin. Nonetheless, DOACs can have clinically relevant pharmacokinetic and pharmacodynamic DDIs. Careful consideration of potential DDIs is needed when prescribing edoxaban, and clinically relevant DDIs may be prevented by avoiding offending combinations, spacing out the timing of the drugs or by halving the dose of edoxaban where indicated.