rivaroxaban and apixaban

Large-scaled post-marketing surveillance studies (PMSSs) of 4 direct oral anticoagulants (DOACs) for stroke prevention in non-valvular atrial fibrillation (AF) were conducted since 2011 in Japan, and the results of the last one have recently been published. Each reported a more than acceptable ischemic stroke prevention. The major bleeding rates were also acceptably low and comparable to each other in the PMSSs of dabigatran (J-dabigatran), rivaroxaban (XAPASS), and edoxaban (ETNA-AF-Japan). However, the incidence in PMSS of apixaban (STANDARD) was more than double the others. This finding appeared to contradict the globally accepted theory that apixaban is less likely than other DOACs to cause bleeding events. Possible responsible mechanisms included (1) the age and kidney function, (2) concomitant antiplatelet therapy, (3) drug actions, (4) follow-up duration, and (5) dose reduction criteria. Similarities in the clinical background shared by the 4 different PMSSs' participants and knowledge from previous studies did not support a dominant contribution of any of those former 4 factors to the increased major bleeding incidence in STANDARD. A possibility of the 5th factor was then examined. An estimated calculation we created showed that apixaban's dose reduction criteria was strict enough to considerably reduce the opportunity for participants to take its reduced rather than standard dose. We then successfully simulated how the "strict" dose reduction criteria would have increased the bleeding event rates under DOAC therapy. The discussion in this review may therefore raise a question about the validity of the current dose reduction criteria of apixaban for Japanese AF patients.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Hemorrhage; Humans; Incidence; Japan; Product Surveillance, Postmarketing; Pyridones; Rivaroxaban; Stroke

Although guidelines give preference to direct oral anticoagulants (DOACs) over vitamin K antagonists (VKAs) for stroke prevention in most patients with atrial fibrillation (AF), DOACs are not recommended in those with rheumatic heart disease or mechanical heart valves. The results of the INVICTUS trial (Investigation of Rheumatic AF Treatment Using Vitamin K Antagonists, Rivaroxaban or Aspirin Studies), which compared rivaroxaban with a VKA in patients with rheumatic heart disease-associated AF, and the PROACT Xa trial (A Trial to Determine if Participants with an On-X Aortic Valve Can be Maintained Safely on Apixaban), which compared apixaban with warfarin in patients with an On-X valve in the aortic position, support the use of VKAs for these indications. In this paper, we review the results of these trials, provide perspective on why VKAs were superior to DOACs, and discuss future directions for anticoagulation in these disorders.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Fibrinolytic Agents; Humans; Pyridones; Rheumatic Heart Disease; Rivaroxaban; Stroke; Vitamin K; Warfarin

Altered direct oral anticoagulant (DOAC) plasma levels can lead either to spontaneous hemorrhagic or thrombotic complications. We describe a case of suspected altered apixaban disposition in a patient with an upper gastrointestinal cancer resection treated with apixaban for non-valvular atrial fibrillation. Diagnosis of ischemic stroke for left hemiparesis was confirmed due to recent emergence of a hypodense area in the posterior capsular nucleus of ischemic reference in a context of binuclear capsular lacunar lesions. Thus, apixaban underexposure was suspected from anamnestic data and oral anticoagulation was switched to parenteral at the next scheduled dose for stroke recurrence. Before switching apixaban pharmacokinetic analysis was performed and unexpectedly showed apixaban plasma overexposure. After 3 days from the switch, the patient experienced spontaneous bleeding complications, for which the risk-benefit profile of continuing anticoagulant treatment for stroke recurrences warranted treatment discontinuation. Unexpected DOAC plasma exposure may present in special patient populations with thrombotic and bleeding complications. Though universally recognized therapeutic ranges have yet to be established for DOACs, periodic drug monitoring may aid in guiding optimization of DOAC therapy and reduce the risk of adverse events in special patient populations.

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

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

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

With the increasing incidence of thromboembolism in children and improvement in management for patients with medically complex diseases, expanded availability of safe and effective anticoagulant medications is needed. Traditionally, the most common anticoagulants used for the treatment or prevention of venous thromboembolism or embolic stroke in children were either unfractionated heparin or the low-molecular-weight heparins. These medications require either intravenous access or daily subcutaneous injections, in addition to multiple venepunctures to monitor drug concentrations. Direct oral anticoagulants provide an alternative, and potentially safer, choice for children, as they are available in oral formulations and do not require drug monitoring. With the approval of the direct factor Xa inhibitor, rivaroxaban (by the European Medicines Agency and Health Canada), and the direct thrombin inhibitor, dabigatran (by the European Medicines Agency and US Food and Drug Administration), the field of paediatric anticoagulation is changing. In this Review, we provide an overview of the four direct oral anticoagulants approved in adults for the treatment and prevention of thrombosis and the completed and ongoing paediatric trials.

Topics: Antithrombins; Child; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Humans; Pediatrics; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles

Rivaroxaban and apixaban are the most widely used nonvitamin K oral anticoagulants (NOACs) in patients with venous thromboembolism (VTE). This meta-analysis evaluates the effectiveness and safety of both NOACs versus standard of care (SoC) in real-world practice.. Real-world evidence (RWE) studies were identified through a systematic literature review conducted between January 2012 and July 2020, using Embase, MEDLINE, and the websites of cardiological, hematological, and oncological associations. Eligible RWE studies recruited adult patients with deep vein thrombosis and/or pulmonary embolism and presented a comparison between rivaroxaban and apixaban versus SoC, consisting either of vitamin K antagonists, heparins, or combinations thereof. Hazard ratios (HRs) for the comparison between NOACs and SoC were extracted from the relevant studies or estimated based on the reported binary data. The between-treatment contrasts were reported as HRs with associated 95% confidence intervals.. A total of 65 RWE studies were identified and considered relevant for the meta-analysis. Compared with SoC, both rivaroxaban and apixaban were associated with reduced risks of recurrent VTE and a lower rate of major bleeding events. Patients treated with rivaroxaban were at a lower risk of all-cause death compared with those receiving SoC (HR = 0.56 [0.39-0.80]), while evidence for apixaban from the identified studies was insufficient to demonstrate a statistically significant change in mortality (HR = 0.66 [0.30-1.47]).. This analysis indicates that in real-world practice, rivaroxaban and apixaban are associated with a lower risk of recurrent VTE and major bleeding events compared with SoC. Survival benefit in patients treated with rivaroxaban was also observed.

Topics: Administration, Oral; Anticoagulants; Hemorrhage; Humans; Pyrazoles; Pyridones; Rivaroxaban; Treatment Outcome; Venous Thromboembolism

Summarize the studies evaluating the use of 4-factor prothrombin complex concentrates in the management of apixaban and rivaroxaban associated intracranial hemorrhages.. A PubMed literature search was conducted for articles published between 2013 and 2020 which contained the following terms in their title: (1) apixaban, rivaroxaban, or factor Xa inhibitor*, and (2) prothrombin complex concentrate*.. Eighteen observational studies were included. When a ∼25 units/kg (range: 25-26.9 units/kg) non-activated 4 factor prothrombin complex concentrate dose was administered, the hemostatic effectiveness rates were ≥ 79% in 2/4 studies that utilized the Sarode et al criteria, in comparison to 4/5 studies that administered a 50 units/kg dose. The mortality rates were < 20% in 7/9 studies with hemostatic effectiveness rates ≥ 79%. Mortality rates were lower in the studies demonstrating higher hemostatic effectiveness rates and including patients with higher Glasgow coma scale scores and lower intracerebral hemorrhage volumes. Overall, the thromboembolic event rates were 0-18%, with 16/18 studies demonstrating rates ≤ 10%. The thromboembolic event rates were not dose or agent dependent.. Rates of hemostatic effectiveness were influenced by the definition of hemostatic effectiveness, dose administered, and patient severity. Studies suggest that higher doses may result in higher hemostatic effectiveness rates without increasing the risk of experiencing a thromboembolic event. This review may be used by providers to modify or validate their reversal strategy approach until well designed studies are available.

Topics: Anticoagulants; Blood Coagulation Factors; Factor Xa Inhibitors; Hemostatics; Humans; Intracranial Hemorrhages; Prothrombin; Retrospective Studies; Rivaroxaban; Thromboembolism

Limited data are available for the comparison between different non-vitamin K antagonist oral anticoagulants (NOACs) on clinical outcomes. We aimed to provide evidence of different NOACs for patients with non-valvular atrial fibrillation (NVAF).. Electronic databases were searched from inception through 22 March 2020 to identify eligible studies in which clinical outcomes (stroke, systemic embolism [SE], bleeding or death events) were directly compared between different NOACs.. 29 real-world studies enrolled more than 700,000 patients were included. Compared with dabigatran, apixaban had higher risk of death (OR 1.07), major bleeding (1.43), GI bleeding (1.64), ischaemic stroke and stroke/SE events (1.10); rivaroxaban had higher risk of death (1.28), major bleeding (1.24), GI bleeding (1.14) and ischaemic stroke (1.08). Compared with rivaroxaban, apixaban had lower risk of death (0.8), major bleeding (0.56) and ischaemic stroke events (0.71). Compared with edoxaban, rivaroxaban had higher risk of major bleeding (2.83), GI bleeding (5.18) and ischaemic stroke (2.28).. In view of the global burden of disease and the routine use of NOACs worldwide, the findings have immediate and important implications. Our data suggested that apixaban might be the priority choice in prevention of bleeding and stroke and dabigatran could be the priority choice in prevention of death events.. This systematic review and meta-analysis were conducted and reported according to the Preferred Reporting Items for Systematic Reviews (PRISMA), Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines and was registered with PROSPERO (CRD42019140553).

Topics: Anticoagulants; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Ischemic Stroke; Pyrazoles; Pyridones; Rivaroxaban; Thrombosis

Venous thromboembolism (VTE) is a frequent cause of morbidity and mortality in patients with cancer. Moreover, management of VTE is frequently connected with complications, namely risk of recurrent VTE and bleeding. Low molecular weight heparins (LMWH) therapy administrated for 3-6 months is currently considered a standard for the treatment of cancer-associated VTE (CA-VTE). Direct oral factor Xa inhibitors (FXaI) apixaban, edoxaban and rivaroxaban have emerged as a new possibility for long-term antithrombotic therapy for VTE. These agents expose several advantages in individuals with cancer, and might overcome several disadvantages connected with LMWH therapy.. First clinical studies with oral FXaI for the treatment of CA-VTE with very promising results were recently published. The article summarizes current data regarding the use of oral FXaI in the treatment of CA-VTE.

Topics: Administration, Oral; Factor Xa Inhibitors; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thrombosis; Venous Thromboembolism

Nonvitamin K oral anticoagulants (NOACs) or direct oral anticoagulants comprise inhibitors of factor Xa (rivaroxaban, apixaban, edoxaban) or factor IIa (dabigatran). Both classes efficiently interfere with the final or penultimate step of the coagulation cascade and showed superior net clinical benefit compared with vitamin K antagonists for prevention of thromboembolic events in patients with AF and for prevention and therapy of deep vein thrombosis and pulmonary embolism. None the less, accumulating data suggested, that there may be differences regarding the frequency of atherothrombotic cardiovascular events between NOACs. Thus, the optimal individualized NOAC for each patient remains a matter of debate. Against this background, some basic and translational analyses emphasized NOAC effects that impact on platelet activity and arterial thrombus formation beyond inhibition of plasmatic coagulation. In this review, we will provide an overview of the available clinical and translational evidence for so-called noncanonical NOAC effects on platelet activation and arterial thrombosis.

Topics: Animals; Blood Coagulation; Dabigatran; Factor Xa Inhibitors; Humans; Platelet Activation; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thrombosis

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

Anticoagulant treatment in non-valvular atrial fibrillation (AF) patients with severe chronic kidney disease (CKD) or on dialysis remains a matter of debate. The object of this study was to quantify the benefit-risk profiles of rivaroxaban or apixaban versus warfarin in AF patients with stage 4-5 CKD or on dialysis.. A comprehensive search of the Cochrane Library, PubMed, Ovid, and Google Scholar databases was performed for eligible studies that comparing the effect and safety of rivaroxaban or apixaban versus warfarin in AF patients with stage 4-5 CKD or on dialysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were abstracted, and then pooled using a random-effects model.. A total of seven studies, one post hoc analysis of RCT and six observational cohorts, were included in this meta-analysis. Compared with warfarin use, the use of rivaroxaban or apixaban was significantly associated with reduced risks of all-cause death (HR = 0.82, 95% CI 0.72-0.93) and gastrointestinal bleeding (HR = 0.87, 95% CI 0.80-0.95). There were no significant differences in the risks of stroke or systemic embolism (rivaroxaban, HR = 0.71, 95% CI 0.43-1.19; apixaban, HR = 0.86, 95%CI 0.68-1.09) and major bleeding (rivaroxaban, HR = 0.96, 95% CI 0.64-1.45; apixaban, HR = 0.56, 95%CI 0.28-1.12).. Current evidence suggests that rivaroxaban or apixaban are safe and at least as effective as warfarin in patients with AF and stage 4-5 CKD or on dialysis.

Topics: Anticoagulants; Atrial Fibrillation; Embolism; Hemorrhage; Humans; Patient Acuity; Pyrazoles; Pyridones; Renal Dialysis; Renal Insufficiency, Chronic; Rivaroxaban; Stroke; 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

The increasing availability of real-world evidence (RWE) about safety and effectiveness of direct non-vitamin K oral anticoagulants (DOACs) for the management of atrial fibrillation (AF) offers the opportunity to better understand the clinical and economic implications of DOACs versus vitamin K antagonists (VKAs). The objective of this study was to compare the economic implications of DOACs and VKAs using data from real-world evidence in patients with AF.. A Markov model simulating the lifetime course of patients diagnosed with non-valvular AF was used to evaluate the cost-effectiveness of DOACs (i.e., rivaroxaban, dabigatran and apixaban) versus VKAs from the Italian National Health System (INHS) perspective. The model was made up of data from the literature and a meta-analysis of RWE on the incidence of stroke/systemic embolism (SE), major bleeding (MB), intracranial haemorrhage (ICH) and all-cause mortality (ACM); direct costs included drug costs, costs for drug monitoring, and management of events from official national lists. One-way and probabilistic sensitivity analyses (PSA) were used to assess the robustness of the results.. Results from the meta-analysis showed that apixaban had a high probability of being the most effective for stroke/SE, MB and ACM. Despite their higher acquisition costs, the cost-effectiveness analysis showed all DOACs involved a saving when compared with VKAs, with per-patient savings ranging between €4647 (rivaroxaban) to €6086 (apixaban). Moreover, all DOACs indicated a gain both in quality-adjusted life-years and life-years. According to PSA, findings related to apixaban were consistent, while for dabigatran and rivaroxaban PSA revealed a higher degree of uncertainty.. The beneficial effect of DOACs on containing events showed in RWE had the potential to offset drug-related costs, thus improving the sustainability of treatment for non-valvular AF in daily clinical practice.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Cost-Benefit Analysis; Dabigatran; Female; Hemorrhage; Humans; Italy; Male; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Vitamin K

Several observational studies have compared the effect of the non-vitamin K antagonist oral anticoagulants to each other in patients with atrial fibrillation. However, confounding by indication is a major problem when comparing non-vitamin K antagonist oral anticoagulant treatments in some of these studies. This meta-analysis was conducted to compare the effectiveness and safety between non-vitamin K antagonist oral anticoagulant and non-vitamin K antagonist oral anticoagulant by only including the propensity score matching studies.. We systematically searched the PubMed and Ovid databases until May 2020 to identify relevant observational studies. Hazard ratios (HRs) and 95% CIs of the reported outcomes were collected and then pooled by a random-effects model complemented with an inverse variance heterogeneity or quality effects model.. A total of 17 retrospective cohort studies were included in this meta-analysis. Compared with dabigatran use, the use of rivaroxaban was significantly associated with increased risks of stroke or systemic embolism (HR, 1.16 [95% CI, 1.05-1.29]) and major bleeding (HR, 1.32 [95% CI, 1.24-1.41]), whereas the use of apixaban was associated with a reduced risk of major bleeding (HR, 0.78 [95% CI, 0.67-0.90]) but not stroke or systemic embolism (HR, 0.84 [95% CI, 0.56-1.28]). Compared with rivaroxaban use, the use of apixaban was associated with a decreased risk of major bleeding (HR, 0.63 [95% CI, 0.54-0.73]) but not stroke or systemic embolism (HR, 0.83 [95% CI, 0.67-1.04]). Reanalyses with the inverse variance heterogeneity or quality effects model produced similar results as the random-effects model.. Current observational comparisons with propensity score matching methods suggest that apixaban might be a better choice compared with dabigatran or rivaroxaban for stroke prevention in atrial fibrillation patients.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Humans; Observational Studies as Topic; Propensity Score; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thromboembolism

A systematic literature review (guided by PRISMA) was performed through January 27, 2021 using PubMed, Embase, and Scopus. Key search term clusters included drug and weight-related concepts (overweight/obese, body mass index [BMI], waist circumference). DistillerSR was utilized to review and process search results. Studies met inclusion if they analyzed the risk of bleeding and/or thrombosis in patients with increased body mass (i.e., via BMI or other criteria) receiving rivaroxaban or apixaban. Clinical guidelines, case reports/series, pharmacokinetic/dynamic analyses, and commentaries were excluded. Bias was examined qualitatively across studies.. After duplicates were removed, the original search rendered 1822 abstracts and 200 full-texts for screening, ultimately providing a final set of 24 studies for qualitative review. Of these studies, 13 (54.2%) enabled comparisons between patients of increased versus normal body mass, while 11 (45.8%) reported outcomes only for patients of increased body mass. The working definition of 'increased body mass' varied amongst the studies, including 11 (45.8%) studies that utilized BMI, seven (29.2%) with a combination of BMI and body measurement, two (8.3%) that relied on body weight alone, and four (16.7%) that identified obesity-related ICD codes. All 13 comparative studies found similar or reduced rates of safety and efficacy outcomes with rivaroxaban and apixaban.. The literature reports similar or lower bleeding and thrombotic risk for rivaroxaban and apixaban in patients of increased body mass compared to patients of normal body mass. Future prospective controlled studies are needed to further define guidelines for use in this population.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Body Mass Index; Hemorrhage; Humans; Pyrazoles; Pyridones; Rivaroxaban; Warfarin

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

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

The involvement of the intestinally expressed xenobiotic transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) have been implicated in rivaroxaban disposition based on in vitro studies, similar to what had previously been proposed for apixaban. We recently showed that these efflux transporters were not clinically relevant for apixaban disposition and examine here their relevance for this second Factor Xa inhibitor.. Using recently published methodologies to discern metabolic- from transporter- mediated drug interactions, a critical evaluation was undertaken of 9 rivaroxaban studies reporting 12 DDIs, one study of food effects and one study of hepatic function.. Rationale examination of these clinical studies using basic pharmacokinetic theory finds little support for the clinical significance of intestinal efflux transporters in rivaroxaban disposition. Drug-drug interactions are most likely adequately predicted based on the level of CYP 3A metabolism.. These analyses indicate that inhibition of efflux transporters appears to have negligible, clinically insignificant effects on the rivaroxaban absorption process, which is consistent with the concern that predictions based on in vitro measures may not translate to a clinically relevant interaction in vivo. We emphasize the need to evaluate gastric emptying, dissolution and other processes related to absorption when using MAT changes to indicate efflux transporter inhibition.

Topics: Administration, Oral; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; Drug Interactions; Drug Liberation; Factor Xa Inhibitors; Gastric Emptying; Gastrointestinal Absorption; Humans; Intestinal Mucosa; Neoplasm Proteins; Pyrazoles; Pyridones; Rivaroxaban; Tissue Distribution

There are limited data regarding the safety of direct oral anticoagulants (DOACs) during breastfeeding. The aim of the present study is to investigate the extent of excretion of DOACs into human milk according to the available clinical and experimental studies.. On 16th January 2021, we systematically searched PubMed, Scopus, Embase, and Web of Science for all studies which investigated DOACs in breastfeeding without any time frame and language limitation. Search keywords were [breastfeeding, breast feeding, breastfed, lactation, milk secretion OR milk] AND [apixaban OR Eliquist OR rivaroxaban OR Xarelto OR edoxaban OR Savaysa OR dabigatran OR Pradaxa OR dabigatran etexilate OR dabigatran etexilate mesylate OR direct oral anticoagulant OR DOAC OR new oral anticoagulant OR NOAC]. Finally, we identified six articles which reported DOAC use during breastfeeding or lactation.. According to the available limited data, dabigatran has the least excretion in human breast milk. Rivaroxaban and dabigatran both have acceptable milk excretion cutoffs, whereas apixaban milk excretion is greater than the maximum allowed range. Further well-designed studies with larger sample sizes are required to generate consistent comparable data and clarify benefits and risks of each DOAC during breastfeeding.

Topics: Anticoagulants; Breast Feeding; Dabigatran; Factor Xa Inhibitors; Female; Humans; Milk, Human; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles

The use of warfarin in patients with atrial fibrillation (AF) and end-stage renal disease (ESRD) has been implicated with efficacy and safety concerns. Evidence on the role of direct oral anticoagulants (DOACs) in this population is limited.. Electronic databases were searched and articles comparing the safety and efficacy of warfarin with apixaban or rivaroxaban were identified. Pooled hazard ratios (HR) were computed using a random-effects model.. A total of eight articles consisting of 30,806 patients; (rivaroxaban 2196, apixaban 2745 and warfarin 25,865) were identified. The pooled HR for major bleeding events favored apixaban over warfarin (0.53, 95% confidence interval (CI) 0.33-0.84, p = 0.008). Apixaban was similar to warfarin in terms of clinically relevant non-major bleeding (HR 1.08, 95% CI 0.64-1.84, p = 0.77) and stroke events (HR 1.09, 95% CI 0.85, 1.39, p = 0.99). There was no significant difference in the risk of major bleeding events (HR 0.95, 95% CI 0.50-1.81, p = 0.88) and stroke between rivaroxaban (HR 1.39, 95% CI, 0.59-3.29, p = 0.09) and warfarin. The combined results of major bleeding in the apixaban group were not affected by the sensitivity analysis.. Apixaban may have a lower risk of major bleeding and comparable risk of stroke when compared with warfarin in AF patients with ESRD.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Humans; Kidney Failure, Chronic; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Warfarin

The optimal antithrombotic strategy for patients with a long-term indication for anticoagulation and acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) remains controversial. This meta-analysis aims to compare randomised trials' outcomes of these patients, focussing on dual versus triple antithrombotic and non vitamin K oral anticoagulants (NOACs) versus vitamin K oral anticoagulants regimens.. Medline, Embase and Cochrane databases were searched from January 1980 to March 2019 yielding 309 articles, and after careful screening, five randomized trials totalling 10 643 patients were included for analysis.. Dual antithrombotic regimens were associated with significantly less thrombolysis in myocardial infarction (TIMI) major and minor bleeding [odds ratio (OR) 0.53, 95% confidence interval (CI) 0.40-0.71], with no significant difference in major adverse cardiovascular events (OR 0.93, 95% CI 0.72-1.22) or all-cause mortality (OR 0.89, 95% CI 0.61-1.19). NOAC regimens had significantly lower TIMI major and minor bleeding (OR 0.58, 95% CI 0.43-0.78) and intracranial bleeding (OR 0.33, 95% CI 0.16-0.66), with similar rates of major adverse cardiovascular events (OR 1.00, 95% CI 0.86-1.16) and all-cause mortality (OR 1.01, 95% CI 0.81-1.26).. Dual antithrombotic and NOAC regimens have reduced bleeding without compromising the risk of cardiovascular events or mortality, and should be preferred for patients with ACS or PCI also needing long-term anticoagulation.

Topics: Acute Coronary Syndrome; Anticoagulants; Aspirin; Atrial Fibrillation; Clopidogrel; Dabigatran; Drug Therapy, Combination; Dual Anti-Platelet Therapy; Factor Xa Inhibitors; Hemorrhage; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Ticagrelor; Warfarin

Traditionally, venous thromboembolism (VTE) resulting from major transient risk factors (e.g., surgery or trauma) or a major persistent risk factor such as cancer, has been defined as being provoked, whereas unprovoked VTE encompasses events without an identifiable cause. These categorizations influence anticoagulant treatment duration; unlike VTE provoked by major transient risk factors, extended anticoagulation beyond 3 months is advised for patients with cancer or unprovoked VTE due to risk persistence after treatment cessation. However, some patients with VTE provoked by minor transient or minor persistent risk factors may also be candidates for extended anticoagulation therapy due to the continuing risk of recurrence. In patients who require extended therapy, vitamin K antagonists (VKAs) are effective but are associated with an increased risk of bleeding and various treatment burdens (e.g., anticoagulation monitoring and dose adjustment). Evaluations of extended VTE treatment with the less-burdensome direct oral anticoagulants such as apixaban, dabigatran, edoxaban, and rivaroxaban show that they are at least as safe and effective as VKAs in a broad range of patients. In addition, apixaban and rivaroxaban offer more than one dosing option, allowing tailoring of treatment to the patient's specific risk factor profile. Analysis of more granular definitions for risk factor groupings has also yielded vital information on the most appropriate strategies for the treatment of patients with specific risk factors, highlighting that extended anticoagulation treatment may benefit those with minor transient and persistent environmental and nonenvironmental risk factors who commonly receive shorter-duration therapy.

Topics: Aged; Anticoagulants; Humans; Patient Selection; Precision Medicine; Pyrazoles; Pyridones; Renal Insufficiency; Risk Factors; Rivaroxaban; Venous Thromboembolism; Vitamin K; Withholding Treatment

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

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

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

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

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

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

To review the literature on treatment of venous thromboembolism (VTE) and prevention of cardioembolic stroke with direct-acting oral anticoagulants (DOACs) in low- and high-body-weight patients and to make recommendations regarding agent selection and dosing in these patient populations.. The selection and optimal dosing of DOACs in low- and high-body-weight patients has not yet been fully elucidated by clinical trials; however, evidence suggests that issues of both safety and efficacy in patients at the extremes of body weight may warrant careful consideration when selecting a DOAC for such patients. This review provides a thorough discussion of the use of DOACs in the treatment of VTE and prevention of cardioembolic stroke in patients at the extremes of body weight and provides guidance regarding agent selection.. While the published evidence on use of DOACs in patients at extremes of body weight is sparse, apixaban and rivaroxaban appear to have the most favorable safety and efficacy profiles. Edoxaban and dabigatran should be avoided.

Topics: Anticoagulants; Body Weight; Dabigatran; Drug Dosage Calculations; Factor Xa Inhibitors; Humans; Obesity; Overweight; Pyrazoles; Pyridones; Rivaroxaban; Venous Thromboembolism

Evidence regarding safety and efficacy of oral anticoagulants for the treatment of atrial fibrillation (AFib) in older adults has been assessed regarding the age appropriateness of oral anticoagulants (OAC) according to the FORTA (Fit fOR The Aged) classification (OAC-FORTA). Three years after its first version (OAC-FORTA 2016), an update was initiated to create OAC-FORTA 2019.. A structured review of randomized controlled clinical trials and summaries of individual product characteristics was performed to detect newly emerged evidence on oral anticoagulants in older patients with AFib. This review was used by an interdisciplinary panel of European experts (N = 10) in a Delphi process to label OACs according to FORTA.. A total of 202 records were identified and 11 studies finally included. We found four new trials providing relevant data on efficacy and safety of warfarin, apixaban, dabigatran or rivaroxaban in older patients with AFib. In the majority of studies comparing the non-vitamin-K oral anticoagulants (NOACs) with warfarin, NOACs were superior to warfarin regarding at least one relevant clinical endpoint. The mean consensus coefficient significantly increased from 0.867 (OAC-FORTA 2016) to 0.931 (p < 0.05) and the proposed FORTA classes were confirmed in all cases during the first round (consensus coefficient > 0.8). Warfarin, dabigatran, edoxaban and rivaroxaban were assigned to the FORTA B label, acenocoumarol, fluindione and phenprocoumon were labeled FORTA C and only apixaban was rated as FORTA A.. OAC-FORTA 2019 confirms that AFib can be successfully treated with positively labeled antithrombotics at advanced age.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Consensus Development Conferences as Topic; Dabigatran; Europe; Female; Humans; Long-Term Care; Male; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Vitamin K; Warfarin

Decisions surrounding periprocedural anticoagulation management must balance thromboembolic and procedural bleed risk. The interruption of both warfarin and DOACs requires consideration of anticoagulant pharmacokinetics, procedural bleed risk and patient characteristics. There is a diminishing role for periprocedural bridging LMWH overall and no role for bridging LMWH for the procedural interruption of DOACs. A clinical approach to perioperative DOAC management based on operative bleeding risk and renal function is safe and effective, and at present, is preferred over preprocedural DOAC levels testing. Clear communication of the anticoagulation interruption plan to both the patient and the patient's care team is essential.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Perioperative Care; Postoperative Complications; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Rivaroxaban; Stroke; Surgical Procedures, Operative; Warfarin

We aimed to review the interfering effect of DOACs on tests for haemostatic function and then to discuss overcoming these with activated carbon (AC) products, thereby eliminating DOAC issues from test plasmas. Recent relevant articles were reviewed and are discussed. Laboratory tests for DOACs, lupus anticoagulant, factor assays and APC Resistance were carried out in such publications with and without an AC product on various instruments using reagents approved for diagnostic use in well-regulated clinical laboratories. All reports on this plasma pre-treatment by AC products agree that they extract DOACs from plasma samples with minimal effect on underlying clotting tests. The specific extraction of DOACs significantly reduced false positive lupus anticoagulant detection and provided more reliable results in clotting factor assays, APC resistance and other thrombophilia tests. Dabigatran and edoxaban seem to be adsorbed more thoroughly by AC from plasmas than rivaroxaban and apixaban. In summary, most of the AC products reviewed here appear to remove DOACs from test plasmas without significantly affecting underlying clotting tests and permit correct diagnosis of various haemostatic conditions despite the initial presence of DOACs. The application of such agents as a sample pre-treatment to overcome the effects of DOACs for routine coagulation testing is supported by the emerging literature.

Topics: Activated Protein C Resistance; Administration, Oral; Anticoagulants; Blood Coagulation Tests; Charcoal; Humans; Lupus Coagulation Inhibitor; Pyrazoles; Pyridones; Rivaroxaban

The off-label use of direct oral anticoagulants (DOACs) for the treatment of left ventricular thrombi has grown over the past several years given the ease of administration, absence of a requirement for international normalized ratio (INR) monitoring, and freedom from dietary restrictions; however, the evidence for their safety and efficacy is contradictory. We systematically searched PubMed and Google Scholar from January 1, 2009, to April 25, 2020, for studies of DOACs for treatment of left ventricular thrombi. Fifty-three articles (of 1,168 patients) met our inclusion criteria. We found that the studies have reached conflicting results; based on our findings, their routine use for the treatment of left ventricular thrombi cannot be recommended. Adequately powered randomized controlled trials are needed to determine the safest and most effective treatment for left ventricular thrombi.

Topics: Dabigatran; Factor Xa Inhibitors; Heart Diseases; Heart Ventricles; Humans; Off-Label Use; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thrombosis; Treatment Outcome

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

The paper is a narrative review of the literature on the use of direct oral anticoagulants (DOACs) for the VTE treatment in challenging patients: senile age (≥75 years), impaired renal function (estimated glomerular filtration rate ≤50 ml/min), fragility (one of the previous characteristics and/or bodyweight ≤50 kg). The paper discusses the studies of EINSTEIN DVT and PE (rivaroxaban), AMPLIFY (apixaban), HOKUSAI-VTE (edoxaban), RE-COVER I and II (dabigatran) in the focus of the secondary analysis in the pre-specified patient's subgroups, as well as their pooled analyzes and meta-analyzes. Based on the results of this review, it was concluded that in a subgroup of senile age patients, dabigatran increases the risk of major bleeding by 4.8 times and has no advantages over vitamin K antagonists (VKA); rivaroxaban and apixaban retain superiority over VKA on the safety outcomes and reduce the risk of major bleeding by 73% and 77%. In the subgroup of patients with impaired renal function, the use of apixaban and dabigatran is associated with an increase in the risk of major bleeding by 6.5 and 7.3 times, and these DOACs do not have advantages over VKA; rivaroxaban retains its superiority over VKA and reduces the risk of major bleeding by 78%. For fragile patients, a secondary analysis is available only for rivaroxaban, which remains superior to VKA on safety endpoints and reduces the risk of major bleeding by 73%. In the absence of direct comparisons between the available DOACs, the presented data can be used as a rational approach for the choice of appropriate treatment for VTE in challenging patients.. Представлен классический описательный обзор литературы, посвященный проблемам использования прямых оральных антикоагулянтов (ПОАК) для лечения венозных тромбоэмболических осложнений (ВТЭО) у ослабленных пациентов: лиц старческого возраста (≥75 лет), пациентов с нарушенной функцией почек (СКФ ≤50 мл/мин), а также «хрупких» больных, имеющих один или оба из перечисленных признаков наряду с низкой массой тела (≤50 кг). Обсуждаются известные исследования EINSTEIN DVT и PE (ривароксабан), AMPLIFY (апиксабан), HOKUSAI-VTE (эдоксабан), RE-COVER I и II (дабигатран) в фокусе вторичного анализа результатов в искомых подгруппах пациентов, а также работы, объединившие их результаты, и метаанализы. Сделаны выводы, что у больных старческого возраста дабигатран увеличивает риск развития больших кровотечений в 4,8 раза и не имеет преимуществ перед антагонистами витамина К (АВК); ривароксабан и апиксабан сохраняют превосходство над АВК с позиции безопасности и снижают угрозу больших кровотечений на 73 и 77%. У пациентов с нарушенной функцией почек использование апиксабана и дабигатрана ассоциируется с увеличением риска больших кровотечений в 6,5 и 7,3 раза, названные ПОАК не имеют преимуществ перед АВК; ривароксабан сохраняется свое превосходство над АВК и снижает угрозу большого кровотечения на 78%. Для подгруппы «хрупких» пациентов вторичный анализ доступен только для ривароксабана, который сохраняется свое превосходство над АВК с позиции безопасности и снижает риск развития больших кровотечений на 73%. В отсутствие прямых сравнений между доступными ПОАК представленные данные могут использоваться с целью обеспечения рационального подхода к выбору препарата для антикоагулянтной терапии ВТЭО у ослабленных пациентов.

Topics: Administration, Oral; Age Factors; Aged; Antithrombins; Dabigatran; Frail Elderly; Humans; Pyrazoles; Pyridones; Renal Insufficiency; Rivaroxaban; Venous Thromboembolism

There are many anticoagulant test indexes available for direct oral anticoagulants (DOACs), but how to select the appropriate index and the index cutoff values are still controversial. This is the first study, to our knowledge, to assess the association of different coagulation indicators with clinical outcomes among DOACs using a meta-analysis of observational studies.. A medical literature search was conducted using PubMed, Web of Science, EMBASE, ClinicalTrials.gov, and the Cochrane Library from inception to February 2020. Studies that reported relationships between coagulation indexes and clinical outcomes or the diagnostic value of coagulation assays were included in the analysis.. A total of 17 articles (7 meta-analyses and 10 systematic reviews) from 8904 citations were included in the analysis. In the analysis of bleeding events with coagulation indexes for DOACs, for peak prothrombin time level (cutoff value of 19-25 s), the pooled results found a sensitivity of 0.61 (95% CI, 0.44-0.75) and a specificity of 0.71 (95% CI, 0.49-0.86). For rivaroxaban, the trough anti-factor Xa concentration (AXA-C) (cutoff value of 400-500 ng/mL) had a sensitivity of 0.53 (95% CI, 0.16-0.87) and a specificity of 0.87 (95% CI, 0.71-0.94), with a diagnostic odds ratio of 7 (95% CI, 2-32). For apixaban, trough AXA-C had a sensitivity of 0.85 (95% CI, 0.60-0.96) and a specificity of 0.83 (95% CI, 0.52-0.95). The AUC of the AXA-C peak was higher than that of the trough AXA-C for apixaban, with a higher sensitivity and specificity. Compared with trough concentration of anti-factor IIa for dabigatran, the peak concentration had a higher specificity (98%) at the cutoff value of 484 ng/mL. In the analysis of thromboembolic events with coagulation indexes for DOACs, peak and trough prothrombin time values were not typically correlated with subsequent symptomatic venous thromboembolism, without a sensitivity or specificity higher than 90%. Trough AXA-C had a sensitivity of 100% and but a low specificity (<50%) for rivaroxaban-apixaban. Trough AXA-C had a sensitivity of 100% and a specificity of 32% with a cutoff value of 108 ng/mL for dabigatran.. Peak prothrombin time (19-25 s) and AXA-C had a better predictive value on bleeding outcomes for rivaroxaban and apixaban, whereas peak concentration of anti-factor IIa activity can be an indicator for dabigatran. Coagulation indexes might not be a good indicator of thromboembolic events of DOACs. Because the limited studies focused on association of coagulation indicators and clinical outcomes, more studies are needed to verify this in the future.

Topics: Administration, Oral; Blood Coagulation; Blood Coagulation Tests; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Prothrombin Time; Pyrazoles; Pyridones; Rivaroxaban; Venous Thromboembolism

Cancer-associated venous thromboembolism remains an important but challenging aspect in the treatment of patients with cancer. Recently, alternatives to injection of low-molecular-weight heparin (LMWH) have been introduced, the non-vitamin K antagonist oral anticoagulants (NOACs), which could potentially alleviate patients from burdensome daily injections.. This review discusses the available evidence exploring the role of NOACs in the treatment and secondary prevention of cancer-associated venous thromboembolism, from randomized trials, observational data, contemporary guideline recommendations, and patient perspectives.. Edoxaban, rivaroxaban, and apixaban have proven attractive alternatives to LMWH for the treatment of cancer-associated venous thromboembolism. Contemporary guidelines have promptly endorsed the use of NOACs in patients with most cancer types. Nonetheless, issues remain regarding bleeding risk, interactions with medical cancer treatment, and the effectiveness and safety for extended treatment periods. There are head-to-head comparisons of the NOACs, and therefore no data favoring the use of one NOAC over the others. Patient's preferences are highly diverse and should be part of routine considerations when weighing risks and benefits associated with various available anticoagulant drugs.

Topics: Administration, Oral; Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Secondary Prevention; Thiazoles; Venous Thromboembolism

Topics: Atrial Fibrillation; Embolism; Factor Xa Inhibitors; Hemorrhage; Humans; Network Meta-Analysis; Obesity, Morbid; Pyrazoles; Pyridones; Rivaroxaban; Stroke

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

Up to two-thirds of menstruating women experience abnormal uterine bleeding (AUB) when treated with oral anticoagulants. However, the true prevalence of AUB for specific agents remains uncertain, as many of these episodes, while interfering significantly with quality of life and overall health, are not captured by definitions of major bleeding (MB) or clinically relevant nonmajor bleeding (CRNMB) used in clinical trials. A 2017 systematic review determined that women taking rivaroxaban, but not edoxaban or apixaban, had a twofold higher risk of AUB than women taking warfarin. Since then, new data have become available from extension trials, cancer-associated venous thromboembolism trials, pediatric trials, and a few observational studies specifically examining AUB as an outcome. Reported rates of uterine CRNMB were low (around 1%) and similar for rivaroxaban and apixaban in all these studies, and no episodes of uterine bleeding meeting MB criteria were reported. Rates of AUB not meeting MB or CRNMB criteria were much higher, affecting up to 50% of women on rivaroxaban. Only 1 such study included women on apixaban, and no AUB was reported. In pediatric trials, 19% of girls experienced menorrhagia when treated with rivaroxaban. In conclusion, rates of uterine MB and CRNMB were low in all studies, but rates of other types of AUB not meeting these criteria ranged from 15.8% to 50%. We conclude that AUB is underreported due to the limitations of MB/CRNMB criteria despite its substantial impact on quality of life. We urge future investigators to include broader definitions of AUB to better capture the impact of this outcome in menstruating women treated with oral anticoagulants.

Topics: Administration, Oral; Adult; Anticoagulants; Female; Humans; Pyrazoles; Pyridones; Rivaroxaban; Uterine Hemorrhage

Heavy menstrual bleeding (HMB) is a common complication of anticoagulation, affecting ∼70% of menstruating women receiving oral anticoagulants. The risk of HMB is lower with apixaban and/or dabigatran than with rivaroxaban. HMB can result in iron deficiency with or without anemia, increased need for medical interventions, decreased quality of life, and missed school/work. Mainstays of treatment include hormone therapies such as the levonorgestrel intrauterine system, subdermal implant, and other progesterone-based therapies, which can result in decreased blood loss and, in some cases, amenorrhea. Combined hormone therapies can be used while patients continue receiving anticoagulation and are also highly effective for decreasing menstrual blood loss. Rarely, procedure-based interventions such as endometrial ablation may be required. Patients should be evaluated for iron deficiency and anemia and offered supportive therapies as needed. Abbreviating the course of anticoagulation or skipping doses can increase the risk of recurrent venous thromboembolism by as much as fivefold, but switching oral anticoagulants may be considered. Awareness of HMB and careful history taking at each visit are crucial to avoid a missed diagnosis.

Topics: Adult; Anticoagulants; Female; Humans; Levonorgestrel; Menorrhagia; Pyrazoles; Pyridones; Quality of Life; Rivaroxaban; Venous Thromboembolism

Venous thrombotic events frequently complicate major elective arthroplasties such as hip and knee replacements. The risk of proximal deep vein thrombosis and pulmonary embolism is estimated at 5 %. For decades, the use of low-dose heparins for up to 5 weeks post-surgery has helped to reduce the risk of thrombotic complications. In this narrative review, we describe the evidence supporting the use of direct oral anticoagulants (in Switzerland - rivaroxaban and apixaban), whose risk-benefit ratios appears superior to that of heparins, at a lower cost. Hybrid strategies combining a short-term anticoagulant followed by low-dose aspirin are also recommended for patients deemed at low thrombotic risk.. Les thromboses veineuses profondes proximales et les embolies pulmonaires sont des complications redoutées après des interventions électives majeures en chirurgie orthopédique (prothèses totales de la hanche et du genou), avec une incidence cumulée estimée à 5 %. Depuis des décennies, ce risque est réduit par l’utilisation d’héparine à dose préventive jusqu’à 5 semaines postopératoires. Dans cette revue narrative, nous décrivons les évidences motivant l’utilisation des anticoagulants oraux directs (rivaroxaban et apixaban en Suisse) qui semblent présenter un rapport bénéfice-risque supérieur aux héparines, à un coût moindre. Des stratégies hybrides comprenant un anticoagulant puis l’aspirine sont désormais également recommandées chez des patients considérés à bas risque thrombotique.

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Heparin; Humans; Pulmonary Embolism; Pyrazoles; Pyridones; Rivaroxaban; Venous Thromboembolism

The risk of recurrence of venous thromboembolism (VTE) persists after interruption of the initial anticoagulation therapy. New evidence shows that direct oral anticoagulants are effective for extended treatment of VTE and may reduce the risk of all-cause mortality. The optimal duration of anticoagulation after VTE is, however, controversial and complicated by the need for individualised assessment and balance between thrombosis and bleeding risks. Three direct oral anticoagulants (rivaroxaban, apixaban and dabigatran) have been studied for extended treatment of VTE. Dabigatran was shown to be safer than vitamin K antagonists and similarly effective for the prevention of recurrent VTE. Dabigatran, apixaban and rivaroxaban resulted in significant decreases in the rate of recurrent symptomatic VTE when compared to placebo, without a statistically significant difference in the risk of major bleeding. The latest guidelines of the American College of Chest Physicians suggest the use of low-dose aspirin to prevent VTE recurrence in patients who want to stop anticoagulation. In the randomised, double-blind, phase 3 EINSTEIN CHOICE trial, once-daily rivaroxaban at doses of 20 mg or 10 mg and 100 mg of aspirin were compared in VTE patients for whom there was clinical equipoise for extended anticoagulation. Either a treatment dose (20 mg) or a prophylactic dose (10 mg) of rivaroxaban significantly reduced the risk of VTE recurrence without a significant increase in bleeding risk compared with aspirin. The EINSTEIN CHOICE trial included patients with provoked or unprovoked VTE. Patients with VTE provoked by minor persistent or minor transient risk factors enrolled in this trial had not-negligible VTE recurrence rates. These new findings on extended therapy suggest the possibility of anticoagulation regimens at intensities tailored to the patients' risk profiles and VTE characteristics, with a shift of the risk-benefit balance in favour of extended treatment.

Topics: Administration, Oral; Aged; Anticoagulants; Aspirin; Dabigatran; Glycosaminoglycans; Hemorrhage; Humans; Middle Aged; Pyrazoles; Pyridones; Recurrence; Risk Factors; Rivaroxaban; Treatment Outcome; Venous Thromboembolism; Vitamin K

Both apixaban and rivaroxaban have been approved for use in acute venous thromboembolism (VTE). Although indirect comparison through network meta-analyses of randomized trials have been performed to compare the efficacy and safety of these agents, further comparison between these agents was lacking until recently. We sought to systematically review and carry out a meta-analysis of studies to further compare apixaban with rivaroxaban from multiple studies done in the real-world settings. Studies comparing rivaroxaban with apixaban in patients with acute VTE were identified through electronic literature searches of MEDLINE, EMBASE, Scopus, and the Cochrane library up to May 2019. Study-specific risk ratios (RRs) were calculated and combined using a random-effects model meta-analysis. In an analysis involving 24 041 patients, recurrent VTE within 6 months occurred in 56 of 4897 patients (1.14%) in the apixaban group and 258 of 19 144 patients (1.35%) in the rivaroxaban group (RR, 0.89; 95% confidence interval [CI], 0.67-1.19;

Topics: Blood Coagulation; Hemorrhage; Humans; Odds Ratio; Pyrazoles; Pyridones; Rivaroxaban; Treatment Outcome; Venous Thromboembolism

The application of venous thromboembolism (VTE) prophylaxis has been the topic of intense debate in plastic surgery. The overall incidence of VTE is low in plastic surgery patients as compared to other surgical subspecialties but may be higher in the inpatient rather than outpatient plastic surgery populations. The Caprini Risk Assessment Model is the most highly studied and validated tool to assess VTE risk in plastic surgery patients. However, the Caprini model lacks procedure-specific risk assessment and patient-specific risk factor calculations. Due to these limitations, such as the low incidence and the heterogeneous nature of the specialty, trials lacked the power to capture proof of benefit, except in the highest-risk inpatient population. The emerging use of aspirin and novel oral anticoagulants may provide an alternative, as noninferiority in terms of efficacy and safety has been demonstrated in other fields. In this review, the authors intend to summarize the current state of evidence for prevention and explore the modalities available for prophylaxis, including novel oral anticoagulants.

Topics: Administration, Oral; Anticoagulants; Aspirin; Chemoprevention; Heparin, Low-Molecular-Weight; Humans; Incidence; Plastic Surgery Procedures; Postoperative Complications; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Venous Thromboembolism

Current guidelines generally recommend continuation of blood thinning drugs in dermatologic surgery and the previously used "bridging" with subcutaneous or intravenous heparin is obsolete. While the guidelines are increasingly implemented in daily practice, there is still uncertainty concerning the use of the novel direct oral anticoagulants (NOAC = DOAC). In this review, we analyze current developments and formulate concise recommendations for continuation during skin surgery under consideration of individual risk.

Topics: Administration, Oral; Anticoagulants; Dabigatran; Dermatologic Surgical Procedures; Humans; Postoperative Hemorrhage; Practice Guidelines as Topic; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban

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

To assess the effectiveness of direct oral anticoagulants vs vitamin K antagonists in real-life patients with atrial fibrillation.. A systematic review was performed according to Cochrane methodological standards. The results were reported according to the PRISMA statement. The ROBINS-I tool was used to assess risk of bias.. A total of 27 different studies publishing data in 30 publications were included. In the studies with a follow-up up to 1 year, apixaban (HR, 0.93; 95%CI, 0.71-1.20) and dabigatran (HR, 0.95; 95%CI, 0.80-1.13) did not significantly reduce the risk of ischemic stroke vs warfarin, whereas rivaroxaban significantly reduced this risk (HR, 0.83; 95%CI, 0.73-0.94). Apixaban (HR, 0.66; 95%CI, 0.55-0.80) and dabigatran (HR, 0.83; 95%CI, 0.70-0.97) significantly reduced the major bleeding risk vs warfarin, but not rivaroxaban (HR, 1.02; 95%CI, 0.95-1.10), although with a high statistical heterogeneity among studies. Apixaban (HR, 0.56; 95%CI, 0.42-0.73), dabigatran (HR, 0.45; 95%CI, 0.39-0.51), and rivaroxaban (HR, 0.66; 95%CI, 0.49-0.88) significantly reduced the risk of intracranial bleeding vs warfarin. Reduced doses of direct oral anticoagulants were associated with a slightly better safety profile, but with a marked reduction in stroke prevention effectiveness.. Data from this meta-analysis suggest that, vs warfarin, the stroke prevention effectiveness and bleeding risk of direct oral anticoagulants may differ in real-life patients with atrial fibrillation.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Case-Control Studies; Dabigatran; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Hemorrhage; Humans; Male; Middle Aged; Observational Studies as Topic; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Stroke; Treatment Outcome; Vitamin K; Warfarin

Oral anticoagulants are commonly used drugs in patients with CKD and patients with ESKD to treat atrial fibrillation to reduce stroke and systemic embolism. Some of these drugs are used to treat or prevent deep venous thrombosis and pulmonary embolism in patients with CKD who undergo knee and hip replacement surgeries. Warfarin is the only anticoagulant that is approved for use by the Food and Drug Administration in individuals with mechanical heart valves. Each oral anticoagulant affects the coagulation profile in the laboratory uniquely. Warfarin and apixaban are the only anticoagulants that are Food and Drug Administration approved for use in patients with CKD and patients with ESKD. However, other oral anticoagulants are commonly used off label in this patient population. Given the acquired risk of bleeding from uremia, these drugs are known to cause increased bleeding events, hospitalization, and overall morbidity. Each anticoagulant has unique pharmacologic properties of which nephrologists need to be aware to optimally manage patients. In addition, nephrologists are increasingly asked to aid in the management of adverse bleeding events related to oral anticoagulant use in patients with CKD and patients with ESKD. This article summarizes the clinical pharmacology of these drugs and identifies knowledge gaps in the literature related to their use.

Topics: Administration, Oral; Anticoagulants; Antidotes; Antithrombins; Dabigatran; Factor Xa Inhibitors; Humans; International Normalized Ratio; Pyrazoles; Pyridines; Pyridones; Renal Insufficiency, Chronic; Rivaroxaban; Thiazoles; Warfarin

The non-vitamin K antagonist oral anticoagulants (NOACs) have been increasingly prescribed in clinical practice for stroke prevention in patients with nonvalvular atrial fibrillation (AF). Direct comparisons between NOACs in trials are lacking, leaving an important clinical decision-making gap. We aimed to perform a systematic review and meta-analysis to summarize the evidence of observational studies for direct comparative effectiveness and safety amongst NOACs in patients with AF. Conference proceedings and electronic databases including MEDLINE, CINAHL, EMBASE and PUBMED were systematically searched. We included observational studies directly comparing individual NOACs in patients with nonvalvular AF who were aged ≥ 18 years for stroke prevention. Primary outcome included effectiveness outcome (stroke or systemic embolism) and safety outcome (major bleeding). Data were extracted in duplicated by two reviewers independently. A random-effects meta-analysis was conducted to synthesize the data from included observational studies. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to rate the overall quality of evidence for each outcome. Fifteen studies were included for qualitative synthesis, twelve studies for meta-analyses. It was found that rivaroxaban and dabigatran were similar with regard to risk of stroke or systemic embolism (Hazard ratio [HR] = 1.00, 95% CI 0.91-1.10; evidence quality: low), but rivaroxaban was associated with higher risk of major bleeding (HR = 1.39, 95% CI 1.28-1.50; evidence quality: moderate). Compared with apixaban, a significantly higher risk of major bleeding was observed with rivaroxaban (HR = 1.71, 95% CI 1.51-1.94; evidence quality: low). Apixaban was associated with lower risk of major bleeding, in comparison with dabigatran (HR = 0.80, 95% CI 0.68-0.95; evidence quality: low). No differences in risk of stroke or systemic embolism was observed between rivaroxaban versus apixaban, and apixaban versus dabigatran. In this study, apixaban was found to have the most favorable safety profile amongst the three NOACs. No significant difference was observed in risk of stroke or systemic embolism between the NOACs. Such findings may provide some decision-making support for physicians regarding their choices amongst NOACs in patients with AF.Registration PROSPERO (identifier: CRD42016052908).

Topics: Administration, Oral; Aged; Antithrombins; Atrial Fibrillation; Dabigatran; Embolism; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Observational Studies as Topic; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Treatment Outcome

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) are increasingly being used in hospital and outpatient settings as safe alternatives to warfarin. Hypersensitivity reactions have been described for NOACs and can be classified according to Gell and Coombs. We reviewed case reports of possible drug hypersensitivity reactions, noticing a predominance of delayed reactions (both mild and severe) and the absence of cross-reactions to warfarin and low molecu-lar weight heparins. International experience on diagnostic tests is lacking. The vast majority of authors refer to probability scores and rely on biopsy to classify vasculitis and rule out differential diagnoses. We propose to adapt available tests to confirm the patient's reactivity to new anticoagulants. Among in vivo tests, patch testing revealed promising in delayed reactions.

Topics: Anticoagulants; Dabigatran; Drug Hypersensitivity; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles

Atrial fibrillation (AF) increases a patient's stroke risk four- to five-fold. Anticoagulation with the vitamin K antagonist (VKA) warfarin reduces the risk of stroke by 67%, but warfarin carries a significant risk of major bleeding and has unpredictable pharmacodynamics with a narrow therapeutic window, necessitating frequent monitoring of its anticoagulant effect. The non-vitamin K antagonist oral anticoagulants (NOACs) dabigatran, rivaroxaban, apixaban, and edoxaban provide more predictable anticoagulant activity than warfarin with a lower risk of major bleeding, and each is noninferior to warfarin for the prevention of stroke. All have earned regulatory approval in the past eight years. At least one of the NOACs is approved for use in all patients with AF, except those with mechanical valves and rheumatic mitral valve disease, for whom warfarin remains the only option. Recent clinical trials have shown that antithrombotic regimens including NOACs are safe and effective in patients with AF who need potent antiplatelet therapy.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Female; Hemorrhage; Humans; Male; Middle Aged; Prognosis; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Risk Assessment; Rivaroxaban; Stroke; Survival Rate; Treatment Outcome; Warfarin

Novel oral anticoagulants are the cornerstone of therapy for non-valvular atrial fibrillation patients to lower the risk of ischaemic stroke. Given the lack of head-to-head comparisons among oral anticoagulants, a Bayesian analysis was used to evaluate their safety and efficacy based on studies from real-world practice.. The PubMed, Embase, Cochrane and Web of Science databases were searched for relevant studies. Bayesian analyses were conducted to estimate hazard ratios (HR) and 95% credible intervals (CrI) for the safety and efficacy of oral anticoagulants.. In the 22 studies included in our analysis, novel oral anticoagulants exhibited a clear advantage over warfarin in preventing ischaemic stroke, haemorrhagic stroke and, especially, intracranial haemorrhage. Incidence of major bleeding was lowest for apixaban, followed by dabigatran, warfarin and rivaroxaban. Gastrointestinal bleeding risk was lowest for apixaban, followed by warfarin, and was slightly lower for dabigatran than for rivaroxaban with no statistical difference (HR 1.05, 95% CrI 0.99-1.11). Ischaemic stroke risk was lowest for rivaroxaban, followed by apixaban, dabigatran and warfarin (HR 1.13, 95% CrI 1.07-1.20).. In real-world practice, apixaban may represent the optimal treatment in terms of safety and efficacy for patients with non-valvular atrial fibrillation. For patients with high risk of ischaemic events but low bleeding risk, rivaroxaban may be preferable.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Bayes Theorem; Dabigatran; Female; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Proportional Hazards Models; Pyrazoles; Pyridones; Risk; Rivaroxaban; Stroke; Warfarin

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

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

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

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

The purpose of this article is to educate staff nurses and advanced practice nurses the importance of identifying, diagnosing, and making appropriate clinical decisions when treating patients with atrial fibrillation. Atrial fibrillation is a supraventricular arrhythmia characterized by uncoordinated, chaotic electrical activity and deterioration of proper atrial mechanical function, with an irregular ventricular response. Poorly controlled or undiagnosed atrial fibrillation increases the risk of mortality and may decrease quality of life. Identifying and staying abreast of cardiovascular care and current updates in treatment is strongly encouraged as guidelines are revised and updated as new treatments evolve.

Topics: Antithrombins; Atrial Fibrillation; Critical Care Nursing; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Pyrazoles; Pyridones; Rivaroxaban; Stroke

Pulmonary embolism (PE) is a common life-threatening cardiovascular condition, with an incidence of 23 to 69 new cases per 100,000 people each year. For selected low-risk patients with acute PE, outpatient treatment might provide several advantages over traditional inpatient treatment, such as reduction of hospitalisations, substantial cost savings, and improvements in health-related quality of life. This is an update of the review first published in 2014.. To compare the efficacy and safety of outpatient versus inpatient treatment in low-risk patients with acute PE for the outcomes of all-cause and PE-related mortality; bleeding; adverse events such as haemodynamic instability; recurrence of PE; and patients' satisfaction.. The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and AMED databases, and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers, to 26 March 2018. We also undertook reference checking to identify additional studies.. We included randomised controlled trials of outpatient versus inpatient treatment of adults (aged 18 years and over) diagnosed with low-risk acute PE.. Two review authors selected relevant trials, assessed methodological quality, and extracted and analysed data. We calculated effect estimates using risk ratio (RR) with 95% confidence intervals (CIs), or mean differences (MDs) with 95% CIs. We used standardised mean differences (SMDs) to combine trials that measured the same outcome but used different methods. We assessed the quality of the evidence using GRADE criteria.. One new study was identified for this 2018 update, bringing the total number of included studies to two and the total number of participants to 451. Both trials discharged patients randomised to the outpatient group within 36 hours of initial triage and both followed participants for 90 days. One study compared the same treatment regimens in both outpatient and inpatient groups, and the other study used different treatment regimes. There was no clear difference in treatment effect for the outcomes of short-term mortality (30 days) (RR 0.33, 95% CI 0.01 to 7.98, P = 0.49; low-quality evidence), long-term mortality (90 days) (RR 0.98, 95% CI 0.06 to 15.58, P = 0.99, low-quality evidence), major bleeding at 14 days (RR 4.91, 95% CI 0.24 to 101.57, P = 0.30; low-quality evidence) and at 90 days (RR 6.88, 95% CI 0.36 to 132.14, P = 0.20; low-quality evidence), minor bleeding (RR 1.08, 95% CI 0.07 to 16.79; P = 0.96, low-quality evidence), recurrent PE within 90 days (RR 2.95, 95% CI 0.12 to 71.85, P = 0.51, low-quality evidence), and participant satisfaction (RR 0.97, 95% CI 0.90 to 1.04, P = 0.39; moderate-quality evidence). We downgraded the quality of the evidence because the CIs were wide and included treatment effects in both directions, the sample sizes and numbers of events were small, and because the effect of missing data and the absence of publication bias could not be verified. PE-related mortality, and adverse effects such as haemodynamic instability and compliance, were not assessed by the included studies.. Currently, only low-quality evidence is available from two published randomised controlled trials on outpatient versus inpatient treatment in low-risk patients with acute PE. The studies did not provide evidence of any clear difference between the interventions in overall mortality, bleeding and recurrence of PE.

Topics: Acute Disease; Adult; Ambulatory Care; Anticoagulants; Confidence Intervals; Enoxaparin; Hemorrhage; Hospitalization; Humans; Pulmonary Embolism; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban

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

Pulmonary embolism (PE) is the most feared clinical presentation of venous thromboembolism (VTE). Patients with PE have traditionally been treated in hospital; however, many are at low risk of adverse outcomes and current guidelines suggest outpatient treatment as an option. Outpatient treatment of PE offers several advantages, including reduced risk of hospital-acquired conditions and potential cost savings. Despite this, patients with low-risk PE are still frequently hospitalized for treatment. This narrative review summarizes current guideline recommendations for the identification of patients with low-risk PE who are potentially suitable for outpatient treatment, using prognostic assessment tools (e.g. the Pulmonary Embolism Severity Index [PESI] and simplified PESI) and clinical exclusion criteria (e.g. Hestia criteria) alone or in combination with additional cardiac assessments. Treatment options are discussed along with recommendations for the follow-up of patients managed in the non-hospital environment. The available data on outpatient treatment of PE are summarized, including details on patient selection, anticoagulant choice, and short-term outcomes in each study. Accumulating evidence suggests that outcomes in patients with low-risk PE treated as outpatients are at least as good as, if not better than, those of patients treated in the hospital. With mounting pressures on health care systems worldwide, increasing the proportion of patients with PE treated as outpatients has the potential to reduce health care burdens associated with VTE.

Topics: Administration, Oral; Anticoagulants; Cardiology; Drug Approval; Hemodynamics; Hospitalization; Humans; Length of Stay; Outpatients; Practice Guidelines as Topic; Prognosis; Pulmonary Embolism; Pyrazoles; Pyridones; Risk; Rivaroxaban; Treatment Outcome; Venous Thromboembolism

Cancer accounts for 20% of all venous thromboembolism (VTE) worldwide and cancer patients are at four- to sevenfold increased risk of thrombosis compared to non-cancer patients. VTE is also a morbid complication of cancer and its incidence is rising. Thrombosis is also a second leading cause of death in cancer patients. The standard of care management for the prevention and treatment of cancer-associated thrombosis (CAT) remains the administration of low-molecular-weight heparins (LMWHs). In the last decade, five direct oral anticoagulants (DOACs), dabigatran, rivaroxaban, apixaban, edoxaban and betrixaban, have been approved for the treatment and prevention of VTE in the general patient population. In this review, we discuss the results of the already published clinical trials with DOACs in the treatment of CAT and the ongoing clinical trials with DOACs in the prevention and treatment of CAT.

Topics: Administration, Oral; Anticoagulants; Benzamides; Dabigatran; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiazoles; Venous Thromboembolism

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

Intracerebral hemorrhage is a major source of morbidity and mortality, accounting for 10% of all strokes. Oral anticoagulation therapy, while necessary to prevent thromboembolic complications, increases the risk of intracerebral hemorrhage and can potentially worsen bleeding in cases of acute hemorrhage. Before the introduction of direct oral anticoagulant agents in 2010, warfarin was the only option for oral anticoagulation. These new agents have an improved safety profile compared with warfarin but require different reversal strategies. Anticoagulation reversal in the setting of acute intracerebral hemorrhage is an evolving field. This article covers the most common direct oral anticoagulant medications, various available anticoagulant reversal strategies, and the latest guidelines for anticoagulation reversal in patients with acute intracranial hemorrhage.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Benzamides; Dabigatran; Humans; Intracranial Hemorrhages; Practice Guidelines as Topic; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Rivaroxaban; Thromboembolism; Treatment Outcome

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

Topics: Administration, Oral; Evidence-Based Medicine; Factor Xa Inhibitors; Humans; Neoplasms; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Risk Factors; Rivaroxaban; Treatment Outcome; Venous Thromboembolism

Direct oral anticoagulants (DOACs) are recommended for the prevention of stroke or systemic embolism in nonvalvular atrial fibrillation. Dabigatran, rivaroxaban, apixaban, and edoxaban represent possible alternatives to warfarin in the setting of cardioversion. A literature review was conducted to evaluate the safety and efficacy of DOAC use pericardioversion.. A PubMed and MEDLINE search through August 2017 was conducted using the following search terms alone or in various combinations: dabigatran, rivaroxaban, apixaban, edoxaban, betrixaban, DOAC, NOAC, TSOAC, cardioversion.. All English-language, human studies comparing the safety and efficacy of DOACs with that of other anticoagulants in the setting of cardioversion were eligible for inclusion. References from published articles were reviewed for additional relevant citations for study inclusion. Four retrospective and 2 prospective trials comparing DOACs with warfarin were identified.. The majority of studies included patients undergoing electric cardioversion. Based on current evidence, the DOACs perform similarly to warfarin in the prevention of stroke and systemic embolism, and bleeding rates are comparable.. DOACs may be an attractive alternative to warfarin because of fast onset of action, potentially reducing delay to cardioversion. More robust studies are needed in patients with renal dysfunction and patients undergoing pharmacological cardioversion.

Topics: Anticoagulants; Atrial Fibrillation; Dabigatran; Electric Countershock; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles

The characteristics and natural history of acute non-vitamin K antagonists oral anticoagulants (NOAC)-associated intracerebral haemorrhage (ICH) are largely unknown. We performed a comprehensive systematic review and meta-analysis to compare baseline ICH volume, haematoma expansion and clinical outcomes between NOAC-ICH versus vitamin K antagonists-ICH (VKA-ICH).. We searched PubMed and conference abstracts for observational studies comparing baseline characteristics and outcomes in patients with NOAC-ICH versus VKA-ICH using an appropriate keyword/MeSH term search strategy. Data were extracted following PRISMA and MOOSE guidelines. The main outcome measures were mortality and unfavourable functional outcome (modified Rankin Score: 4-6) at discharge and at 3 months, as well as ICH volumes and haematoma expansion rates in the two groups. Random-effects models with DerSimonian-Laird weights were used for pooled estimates calculation.. Twelve studies including 393 NOAC-ICH and 3482 VKA-ICH were pooled in meta-analysis. There was no difference in mean ICH-volume between the two groups (standard mean difference: -0.24; 95% CI -0.52 to 0.04, p=0.093). The rates of haematoma expansion were comparable in NOAC-ICH versus VKA-ICH (OR: 0.76; 95% CI 0.49 to 1.19, p=0.236). We did not find any difference between patients with NOAC-ICH versus VKA-ICH in all-cause mortality at discharge (OR: 0.66; 95% CI 0.42 to 1.05, p=0.077) and unfavourable functional outcome at discharge (OR: 0.77; 95% CI 0.41 to 1.44, p=0.413). The 3-month outcome was also comparable between the two ICH groups. Moderate-to-substantial statistical heterogeneity was noted.. Our results confirm that ICH volume, haematoma expansion, mortality and functional outcome appear to be similar for NOAC-ICH versus VKA-ICH. Large prospective cohorts and updated meta-analyses are needed to provide more precise estimates.

Topics: Anticoagulants; Antithrombins; Cerebral Hemorrhage; Dabigatran; Factor Xa Inhibitors; Hematoma; Humans; Mortality; Odds Ratio; Phenprocoumon; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Severity of Illness Index; Thiazoles; Vitamin K; Warfarin

The use of oral anticoagulant therapy for stroke prevention in atrial fibrillation has been transformed by the availability of the nonvitamin K antagonist oral anticoagulants. Real-world studies on the use of nonvitamin K antagonist oral anticoagulants would help elucidate their effectiveness and safety in daily clinical practice. Apixaban was the third nonvitamin K antagonist oral anticoagulants introduced to clinical practice, and increasing real-world studies have been published. Our aim was to summarize current evidence about real-world studies on apixaban for stroke prevention in atrial fibrillation.. We performed a systematic review and meta-analysis of all observational real-world studies comparing apixaban with other available oral anticoagulant drugs.. From the original 9680 results retrieved, 16 studies have been included in the final meta-analysis. Compared with warfarin, apixaban regular dose was more effective in reducing any thromboembolic event (odds ratio: 0.77; 95% confidence interval: 0.64-0.93), but no significant difference was found for stroke risk. Apixaban was as effective as dabigatran and rivaroxaban in reducing thromboembolic events and stroke. The risk of major bleeding was significantly lower for apixaban compared with warfarin, dabigatran, and rivaroxaban (relative risk reduction, 38%, 35%, and 46%, respectively). Similarly, the risk for intracranial hemorrhage was significantly lower for apixaban than warfarin and rivaroxaban (46% and 54%, respectively) but not dabigatran. The risk of gastrointestinal bleeding was lower with apixaban when compared with all oral anticoagulant agents (. Use of apixaban in real-life is associated with an overall similar effectiveness in reducing stroke and any thromboembolic events when compared with warfarin. A better safety profile was found with apixaban compared with warfarin, dabigatran, and rivaroxaban.

Topics: Anticoagulants; Atrial Fibrillation; Clinical Trials as Topic; Female; Humans; Intracranial Hemorrhages; Male; Polymers; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Saliva, Artificial; Stroke; Vitamin K; Warfarin

The significance of adding new oral anticoagulants (NOACs) to antiplatelet therapy in patients with acute coronary syndrome (ACS) is unclear. We conducted a meta-analysis to assess the safety and efficacy of adding NOACs (apixaban, rivaroxaban, and dabigatran) to single antiplatelet agent (SAP) or dual antiplatelet therapy (DAPT) in patients with ACS. Seven randomized controlled trials were selected using PubMed or MEDLINE, Scopus, and Cochrane library (inception to August 2017). The summary measure was random effects hazard ratio (HR) with 95% confidence interval (CI). The primary safety outcome was clinically significant bleeding. The secondary efficacy outcome was major adverse cardiovascular events (MACE; composite of myocardial infarction, stroke, and all-cause mortality). In 31,574 patients, addition of NOAC to SAP did not increase the risk of clinically significant bleeding (HR 0.82, 95% CI 0.56 to 1.20, p = 0.31); however, the risk of clinically significant bleeding was significantly increased with NOAC plus DAPT (HR 2.24, 95% CI 1.75 to 2.87, p < 0.001). NOACs had no statistically beneficial effect on MACE when used with SAP (HR 0.82, 95% CI 0.66 to 1.04, p = 0.10); however, a modest reduction in MACE was observed when NOACs were combined with DAPT (HR 0.86, 95% CI 0.78 to 0.93, p < 0.001). In conclusion, in patients with ACS, the addition of NOAC to DAPT resulted in increased risk of clinically significant bleeding, whereas only a modest reduction in MACE was achieved. The addition of NOACs to SAP did not result in significant reduction of MACE or increase in clinically significant bleeding.

Topics: Acute Coronary Syndrome; Administration, Oral; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Pyrazoles; Pyridones; Rivaroxaban

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

Patients with end-stage renal disease (ESRD) were excluded from pivotal clinical trials with oral anticoagulants. While such patients are at an increased risk of venous and arterial thromboembolism, their risk of bleeding is also elevated. It is thus of little surprise that stroke prevention with vitamin K antagonists (VKAs) in ESRD patients with atrial fibrillation is controversial, with observational evidence ranging from beneficial to harmful. This uncertainty extends to the less studied use of VKAs for venous thromboembolism in ESRD. The direct oral anticoagulants (DOACs) apixaban and rivaroxaban have now permissive labeling in the United States for atrial fibrillation in patients with ESRD; this expanded labeling has not yet occurred either in Europe or for venous thromboembolism. This review summarizes the current evidence for the pharmacology of DOACs in ESRD as well as their utilization and safety in patients with ESRD and atrial fibrillation.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Humans; Kidney Failure, Chronic; Pyrazoles; Pyridones; Rivaroxaban; United States; Venous Thromboembolism; Vitamin K

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

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

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

Dabigatran, rivaroxaban, apixaban and edoxaban are approved novel oral anticoagulants (NOACs) as alternatives to Vitamin K antagonists (VKA). Physicians are prescribing an ever-increasing amount these drugs to their patients due to various advantages over existing medications.. The objective of this review is to provide the dental professional with current literature surrounding the emergence of NOACs, as well as various case studies on the subject, in an effort to guide clinical decision making regarding these medications. The pharmacological profiles of these NOACs and idarucizumab, a reversal agent for dabigatran, will be detailed in this review.. A review of the literature on NOACs was undertaken and the Pubmed, Medline, and Embase databases were used to identify articles published in the English language. Additionally, major dental medicine journals were hand searched, followed by a review of the ClinicalTrials.gov database.. Due to minimal research regarding dental treatment of patients on NOACs and minimal clinical experience of practitioners treating these patients, there is currently insufficient data to establish an evidence-based NOAC management protocol in a dental setting.. In this review, the most significant advantages of NOACs over VKAs was found to be limited interactions with other drugs as well as rapid onset and offset of action.. Despite these benefits, as well as various others, NOACs still lack specific management parameters as well as antidotes or reversal agents. Therefore, dental professionals must use caution when treating patients currently taking these specific anticoagulants.

Topics: Administration, Oral; Anticoagulants; Dabigatran; Dental Care; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles

Acute pulmonary embolism (PE) is a relatively common cardiopulmonary emergency that is a major cause of hospitalization and morbidity and is the primary cause of mortality associated with venous thromboembolism (VTE). During the last decade, one of the biggest changes in the management of PE has been the approval of four non-vitamin K antagonist oral anticoagulants (NOACs; apixaban, dabigatran, edoxaban and rivaroxaban) for the treatment of PE and deep vein thrombosis and secondary prevention of VTE. Areas covered: This article reviews the evolving management of PE in the NOAC era and addresses three fundamental questions: who should receive NOACs over conventional heparin/vitamin K antagonist regimens for the treatment of acute PE; should patients be treated as inpatients or outpatients; and how long should patients be treated to reduce the risk of recurrence? Expert commentary: The management of PE is changing. NOACs provide new anticoagulant treatment options for patients with PE, based on Phase III clinical study results. The consistent efficacy and safety profile of NOACs across many PE patient subgroups, including the elderly, fragile patients, those with active cancer and high-risk (right ventricular dysfunction) patients, suggests NOAC use will increase among these patients.

Topics: Administration, Oral; Anticoagulants; Dabigatran; Humans; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Secondary Prevention; Thiazoles; Venous Thromboembolism

Patients with chronic kidney disease (CKD) are at increased risk of atrial fibrillation, stroke, and bleeding posing unique clinical challenges. Novel oral anticoagulants (NOACs) including dabigatran, rivaroxaban, and apixaban have become recognized as alternative therapy to Vitamin K Antagonists (VKA) regarding the prevention of venous thromboembolism (VTE) and reduce the risk of stroke in atrial fibrillation. However, the understanding of NOACs in CKD is still underdeveloped. This review summarizes recent literature on the efficacy and safety of NOACs in patients with CKD.. Studies focusing on patients with moderate kidney disease were drawn from post hoc analyses from three major NOAC trials, meta-analyses, and postmarketing surveillance studies. Cumulatively, these studies continue to demonstrate NOACs as equivalent if not superior therapies to VKAs in regards to both efficacy and safety. These studies are limited by small sample sizes as well as a lack of direct comparison between NOACs.. The role of NOACs in managing VTE and atrial fibrillation is increasing. Current research suggests that NOACs are at least as efficacious and well tolerated as VKAs. More research is required to elucidate which NOAC is preferable in the clinical setting.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Humans; Pyrazoles; Pyridones; Renal Insufficiency, Chronic; Risk Factors; Rivaroxaban; Stroke; Venous Thromboembolism

Left ventricular (LV) thrombus is commonly seen in patients with extensive anterior ST-elevation myocardial infarction. The standard of care for LV thrombus is anticoagulation with warfarin. However, there has been an increasing trend of case reports using non-vitamin K antagonist oral anticoagulants (NOAC) for the treatment of LV thrombus. This study aimed to perform a meta-summary of the literature to characterise and evaluate the safety and feasibility of using NOAC in patients with LV thrombus. We searched for articles published in four electronic databases: PubMed, EMBASE, Scopus and Google Scholar using an appropriate keyword/MeSH term search strategy. Twenty-four studies comprising 36 patients were included in the analysis. Rivaroxaban was used in majority of patients (47.2%), whilst Apixaban and Dabigatran were prescribed in 25.0% and 27.8% of patients respectively. The most commonly associated risk factor found was post-acute myocardial infarction in 15 patients (41.7%). LV thrombus resolution was met by most patients (87.9%), and the median duration of treatment to resolution was 30.0 days (IQR = 22.5-47.0). One non-fatal bleeding event (3.0%) and no embolic events were reported. The use of NOAC may have a role in the treatment of LV thrombus in selected patients. Further randomized controlled trials are needed to evaluate this treatment strategy.

Topics: Administration, Oral; Anticoagulants; Dabigatran; Hemorrhage; Humans; Myocardial Infarction; Pyrazoles; Pyridones; Rivaroxaban; Thrombosis; Ventricular Dysfunction, Left

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: Administration, Oral; Anticoagulants; Dabigatran; Heart Transplantation; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Warfarin

Essentials Risk of intracranial hemorrhage (ICH) may differ between direct oral anticoagulants (DOACs). We compared the risk of ICH between DOACs using network meta-analysis. Dabigatran 110 mg and 150 mg were safer than rivaroxaban on Bayesian analysis. Dabigatran 110 mg ranked as the safest DOAC while rivaroxaban ranked last.. Background The comparative risk of intracranial hemorrhage (ICH) among direct oral anticoagulants (DOACs) (dabigatran, rivaroxaban, apixaban and edoxaban) remains unclear. Objective To determine the difference in risk of ICH between DOACs Methods Seventeen randomized controlled trials (RCTs) were selected using PubMed/MEDLINE, EMBASE and CENTRAL (Inception, 31 December 2017). Estimates were reported as odds ratio (OR) with 95% credible interval (CR.I) in Bayesian network meta-analysis (NMA), and OR with 95% confidence interval (CI) in traditional meta-analyses. Relative ranking probability of each group was generated based on surface under the cumulative ranking curve (SUCRA). Results In NMA of 116 618 patients from 17 RCTs (apixaban = 19 495 patients, rivaroxaban = 14 157 patients, dabigatran = 16 074 patients, edoxaban = 11 652 patients, and comparator = 55 315 patients), all DOACs were safer than warfarin for risk of ICH. Dabigatran 110 mg ranked as the safest drug (SUCRA, 0.85) and reduced the risk of ICH by 56% compared to rivaroxaban (OR, 0.44; 95% Cr.I, 0.22-0.82). Pairwise meta-analysis validated these findings, showing that DOACs were safer than warfarin (OR, 0.46; 95% CI, 0.35-0.59). Subgroup analysis showed that the benefit was present when DOACs were used in non-valvular atrial fibrillation (NVAF) (OR, 0.51; 95% CI, 0.38-0.68) or venous thromboembolism (VTE) (OR, 0.32; 95% CI, 0.18-0.58). Conclusion Dabigatran 110 mg may be the safest choice among any anticoagulant regarding risk of ICH. Both dabigatran 110 mg and 150 mg were safer than rivaroxaban.

Topics: Administration, Oral; Antithrombins; Bayes Theorem; Dabigatran; Factor Xa Inhibitors; Humans; Intracranial Hemorrhages; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Risk Factors; Rivaroxaban; Thiazoles; Treatment Outcome

Management of atrial fibrillation (AF) in patients with advanced chronic kidney disease (CKD) poses a complex conundrum because of higher risks for both thromboembolic and bleeding complications compared to the general population. This makes it particularly important for clinicians to carefully weigh the risks versus benefits of anticoagulation therapy to determine the individualized net clinical benefit for every patient. During the past few years, 4 non-vitamin K-dependent oral anticoagulant (NOAC) agents have supplemented warfarin in the therapeutic armamentarium for the prevention of systemic thromboembolism in nonvalvular AF. However, the use of NOACs in CKD specifically mandates a nuanced understanding due to their varying dependence on renal clearance, with resultant safety implications related to either underdosing (thromboembolism) or excessive drug exposure (bleeding). This pragmatic review highlights unique considerations pertaining to accurate estimation and temporal monitoring of kidney function in the context of NOAC use with specific clinical deliberations and variables when determining whether an NOAC is appropriate for a patient with CKD. The dependence of NOACs on renal clearance and several troubling safety signals in the published literature suggest that it is vital for nephrologists to be active members of a multidisciplinary team caring for these high-risk patients with CKD and AF.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Cyclophosphamide; Dabigatran; Diabetes Mellitus; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Hypertension; Male; Multimorbidity; Obesity; Prognosis; Pyrazoles; Pyridones; Renal Insufficiency, Chronic; Risk Assessment; Rivaroxaban; Thromboembolism

Novel oral anticoagulants (NOACs) are becoming a therapy of choice in everyday clinical practice after almost 50 years during which warfarin and related coumarin derivatives were used as the main anticoagulants. Advantages of NOACs over standard anticoagulants include their predictable pharmacodynamics and pharmacokinetics, stable plasma concentrations and less drug-drug and food-drug interactions. However, pharmacogenetics has its place in administration of NOACs, as considerable interindividual variations have been detected. In this review, previous findings in pharmacogenetics of dabigatran, rivaroxaban, apixaban and edoxaban are summarized, along with recommendations for studying genes encoding metabolically important enzymes for four selected NOACs. Future directions include identification of clinically relevant SNPs, and change in optimum dosage for patients who are carriers of significant variants.

Topics: Administration, Oral; Anticoagulants; Dabigatran; Enzymes; Humans; Pharmacogenomic Testing; Pharmacogenomic Variants; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles

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

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

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

The Multimorbid Patient: Use of New Oral Anticoagulants in Patients with Chronic Kidney Disease Abstract. Increasing life expectancy in Western countries is associated with a high prevalence of multiple chronic diseases which is defined by the term "multimorbidity". Many of these patients suffer from chronic kidney disease (CKD) and thrombogenic comorbidities such as atrial fibrillation with the need for oral anticoagulation. For decades vitamin K antagonists have been exclusively prescribed for oral anticoagulation. However, due to altered pharmacokinetics and bioavailability of these drugs in CKD, a significant risk of bleeding exists. The introduction of direct oral anticoagulants as a new and promising alternative to vitamin K antagonists was -especially for CKD patients - highly anticipated. However, data from randomized studies are missing for older patients with advanced CKD. Consequently, a careful evaluation of the risk-benefit ratio is recommended for this sensitive patient population.. Zusammenfassung. Die zunehmende Lebenserwartung in den westlichen Ländern führt zu einer gleichzeitigen Zunahme chronischer Krankheiten, was mit «Multimorbidität» bezeichnet wird. Viele dieser Patienten leiden an chronischer Niereninsuffizienz (CKD) sowie thrombogenen Komorbiditäten wie z.B. Vorhofflimmern, weshalb eine orale Antikoagulation indiziert ist. Für lange Zeit standen lediglich die Vitamin-K-Antagonisten zur Verfügung. Aufgrund der unter anderem veränderten Pharmakokinetik sowie Bioverfügbarkeit dieser Medikamente bei CKD besteht jedoch gleichzeitig ein deutlich erhöhtes Blutungsrisiko. Die Einführung der direkten oralen Antikoagulanzien als neue und vielversprechende Alternative zu Vitamin-K-Antagonisten wurde daher insbesondere für die Population der CKD-Patienten mit grosser Spannung erwartet. Aufgrund der noch nicht ausreichenden Datenlage insbesondere bei älteren Patienten mit fortgeschrittener Niereninsuffizienz sollte das Risiko-Nutzen-Verhältnis vor Therapiebeginn sorgfältig evaluiert werden.

Topics: Anticoagulants; Arterial Occlusive Diseases; Atrial Fibrillation; Comorbidity; Contraindications; Coronary Disease; Dabigatran; Glomerular Filtration Rate; Kidney Failure, Chronic; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thromboembolism; Vitamin K

Intravenous andexanet alfa [coagulation factor Xa (recombinant), inactivated-zhzo; Andexxa

Topics: Anticoagulants; Antidotes; Blood Coagulation; Dose-Response Relationship, Drug; Drug Approval; Drug Therapy, Combination; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban; Treatment Outcome; United States; United States Food and Drug Administration

Non-vitamin K antagonist oral anticoagulants (NOACs) might be an attractive choice for stroke prevention in people without atrial fibrillation who may harbor a potential source of cardiac emboli, but not if certain individual NOACs carry risks of intracranial hemorrhage that are heightened relative to aspirin.. To conduct a systematic review and meta-analysis of randomized clinical trials to assess the risk of intracranial hemorrhage with individual NOACs vs aspirin across all indications.. We searched PubMed, Embase, CENTRAL, and ClinicalTrials.gov from inception to May 28, 2018, with the terms novel oral anticoagulants, non-vitamin K antagonist oral anticoagulants, direct oral anticoagulants, dabigatran, rivaroxaban, apixaban, edoxaban, warfarin, Coumadin, vitamin K antagonist, aspirin, acetylsalicylic acid, or ASA, and major bleeding, fatal bleeding, or intracranial hemorrhage. We restricted our search to clinical trials on humans. There were no language restrictions.. Randomized clinical trials of 3 months or longer that included a comparison of the outcomes of NOAC use vs use of aspirin.. Two investigators independently abstracted data from eligible studies. We computed a fixed-effect estimate based on the Mantel-Haenszel method.. Odds ratios (ORs) with 95% CI were used as a measure of the association of individual NOAC vs aspirin with the risk of intracranial hemorrhage. The hypothesis that intracranial hemorrhage risk would be higher with NOACs than aspirin was formulated during data collection.. Our principal analysis included 5 randomized clinical trials comparing 1 or more NOACs with aspirin, with 39 398 individuals enrolled. Pooling the results from the fixed-effects model showed that a dose of 15 to 20 mg of rivaroxaban once daily was associated with an increased risk of intracranial hemorrhage (2 trials; OR, 3.31 [95% CI, 1.42 to 7.72]) compared with aspirin, while a 10-mg dose of rivaroxaban once daily or a 5-mg dose twice daily (3 trials; OR, 1.43 [95% CI, 0.93 to 2.21]) and a 5-mg dose of apixaban twice daily (1 trial; OR, 0.84 [95% CI, 0.38 to 1.88]) were not.. A 15-mg to 20-mg dose of rivaroxaban once daily is associated with substantially increased risks of intracranial hemorrhage, while smaller daily doses of rivaroxaban and apixaban were not, implying that risk increase is dose dependent. It may be worthwhile to conduct randomized clinical trials comparing specific NOACs in specific doses (eg, apixaban, 5 mg twice daily) and aspirin in patients without atrial fibrillation, but with potential sources of cardiac emboli that could cause stroke.

Topics: Anticoagulants; Aspirin; Dose-Response Relationship, Drug; Fibrinolytic Agents; Humans; Intracranial Hemorrhages; Pyrazoles; Pyridones; Rivaroxaban

Solid organ transplant patients are at risk of developing atrial fibrillation and venous thromboembolism. Direct oral anticoagulants are considered an attractive option for anticoagulation in patients due to their convenience; however, strong evidence of their use in transplantation is lacking. We conducted a search using Pubmed, Embase, and Scopus databases, in addition to International Society of Heart and Lung transplantation and American Transplant Congress abstracts (from 2012 through December 2017). Fourteen articles were reviewed that included case reports, retrospective case series, or chart review analyses of small cohorts. Based on this review, the findings can only generate hypotheses that should be further studied in a larger randomized cohort. This review can help clinicians gain insight into the use of direct oral anticoagulant in this special population. For now, clinicians should be cautious about their use in this special population.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cohort Studies; Dabigatran; Female; Humans; Male; Middle Aged; Organ Transplantation; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Venous Thromboembolism

To compare the efficacy and safety of rivaroxaban, apixaban and enoxaparin for thromboprophylaxis after arthroplastic surgery.. We conducted a meta-analysis containing a wide range of randomized controlled trials about efficiency and safety of rivaroxaban, apixaban and enoxaparin for thromboprophylaxis after arthroplastic surgery in the recent decade from January 2006 to June 2018. The present study separately analyzed the following key components: the different efficiency and safety for rivaroxaban and enoxaparin; apixaban and enoxaparin; and enoxaparin and other new developed anticoagulants.. Sixteen studies containing 58885 patients were included. In results of efficacy outcomes, total events occurred in 4.89% patients of rivaroxaban group and 9.55% patients of the control group; however, no significant difference was observed in apixaban groups of their efficacy outcomes. Primary events didn't show significant difference when comparing apixaban with the control or comparing enoxaparin with the control. In analysis of safety outcomes, bleeding events occurred in 3.41% patients of rivaroxaban group compared with 2.84% patients of the control groups; bleeding events in apixaban groups were 4.09% compared with the control groups 4.64%. Bleeding events occurred in 3.51% patients of enoxaparin group, slightly lower than 5.82% of the control group.. Direct oral anticoagulant, rivaroxaban might have better efficacy outcomes in thromboprophylaxis after arthroplastic surgery; however, apixaban showed no significantly different efficacy outcomes compared with enoxaparin, and enoxaparin may have equal or even better safety outcomes compared with direct oral anticoagulants.

Topics: Anticoagulants; Arthroplasty; Enoxaparin; Female; Hemorrhage; Humans; Male; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Venous Thromboembolism

Background and Purpose- Although there are no trials or large cohorts to inform clinical care, current guidelines caution against giving intravenous tPA (tissue-type plasminogen activator) to patients with acute ischemic stroke who are taking non-vitamin K antagonist oral anticoagulants (NOACs). We performed a literature review of intravenous tPA in patients treated with NOACs preceding stroke. Methods- A literature search of PubMed was performed encompassing January 2010 to March 2018. Patient characteristics, timing of last medication intake, laboratory testing, use of reversal, and outcomes ≤3 months after discharge were summarized. Results- We identified 55 studies with 492 NOAC patients receiving tPA (dabigatran, 181; rivaroxaban, 215; apixaban, 40; and unspecified NOAC, 56). Among patients with complete data, the median time from the last NOAC intake to symptom onset was 8 hours (interquartile range, 2.5-14.5), with 55.2% (80/145) within 12 hours. Few patients underwent sensitive laboratory tests, such as thrombin time, diluted thrombin time, or anti-Xa assays before tPA administration. The overall observed rates of symptomatic intracranial hemorrhage, mortality, and favorable outcomes (National Institutes of Health Stroke Scale score, ≤1; modified Rankin Scale score, 0-2; or neurological improvement in the National Institutes of Health Stroke Scale score, ≥8 points) were 4.3% (20/462), 11.3% (48/423), and 43.7% (164/375), respectively. Among dabigatran-treated patients, reversal with idarucizumab was associated with fewer symptomatic intracranial hemorrhage (4.5% [2/44] versus 7.4% [8/108]; unadjusted odds ratio, 0.60; 95% CI, 0.12-2.92), death (4.5% [2/44] versus 12.0% [13/108]; unadjusted odds ratio, 0.35; 95% CI, 0.08-1.61), and more favorable outcomes (79.1% [34/43] versus 39.2% [29/74]; unadjusted odds ratio, 5.86; 95% CI, 2.45-14.00), although the differences were not statistically significant for symptomatic intracranial hemorrhage and death. Conclusions- These preliminary observations suggest that tPA may be reasonably well tolerated without prohibitive risks of bleeding complications in selected patients on NOACs. Reversal of anticoagulant effects by idarucizumab for dabigatran-treated patients before tPA is an emerging strategy that was associated with more favorable outcomes.

Topics: Administration, Intravenous; Administration, Oral; Antibodies, Monoclonal, Humanized; Anticoagulants; Antidotes; Antithrombins; Brain Ischemia; Dabigatran; Factor Xa Inhibitors; Fibrinolytic Agents; Humans; Intracranial Hemorrhages; Odds Ratio; Practice Guidelines as Topic; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Tissue Plasminogen Activator

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

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

Patients with end-stage kidney disease (ESKD) have an elevated incidence of atrial fibrillation (AF) and are at increased risk for thromboembolic events. However, these patients are also at increased risk for bleeding and it is unclear whether they benefit from an oral anticoagulant. Point prevalent on July 1, 2015, only ~28% of dialysis patients with AF were on oral anticoagulation. Warfarin was the most commonly used oral anticoagulant, followed by apixaban, while dabigatran and rivaroxaban were rarely used. This article reviews the current evidence regarding each oral anticoagulant especially as they relate to patients with ESKD.

Topics: Anticoagulants; Atrial Fibrillation; Dabigatran; Humans; Kidney Failure, Chronic; Pyrazoles; Pyridines; Pyridones; Renal Dialysis; Rivaroxaban; Thiazoles; Thromboembolism; Warfarin

Topics: Administration, Oral; Anticoagulants; Dabigatran; Electric Countershock; Humans; Pyrazoles; Pyridines; Pyridones; Risk Factors; Rivaroxaban; Thiazoles; Thromboembolism; Time Factors

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

New oral anticoagulants (NOACs: dabigatran, rivaroxaban, apixaban and edoxaban) proved to be at least non-inferior to warfarin in reducing thromboembolic risk in patients with atrial fibrillation. In addition, NOACs have been demonstrated to be safe and associated with a significant reduction in major and intracranial bleeding events. With the exception of apixaban, an increase in gastrointestinal bleedings has been observed, but as a whole NOACs have been shown to reduce mortality with rates similar to those of warfarin.Currently, NOACs are spreading slowly into clinical practice because of fears among clinicians and regulatory limitations to their prescription. However, efficacy and safety of NOACs have been confirmed by real-world data, also in elderly and frail patients, who represent the majority of treated subjects. Edoxaban has recently been approved by the Food and Drug Administration and the European Medicines Agency and marketed from some months. Real-world data are expected shortly. The large body of evidence in support of NOAC efficacy and safety should lead to an increased use of these new drugs in patients affected by atrial fibrillation.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Humans; Pyrazoles; Pyridines; Pyridones; Registries; Rivaroxaban; Thiazoles; Thromboembolism; Treatment Outcome

Background Haemostasis is crucial for the success of oral surgical treatment as bleeding problems can cause complications both pre- and post-operatively. Patients on anticoagulant drugs present a challenge due to their increased risk of bleeding.Aims To review the evidence for the management of oral surgery patients on novel oral anticoagulant therapy.Methods A literature review was conducted in May 2016 of free-text and MESH searches (keywords: apixaban, dabigatran, rivaroxaban and dental extractions) in the Cochrane Library, PubMed and CINAHL. Trial registers, professional bodies for guidelines and OpenGrey for unpublished literature were also searched. Studies were selected for appraisal after limits were applied (adult, human and English only studies) and inclusion/exclusion criteria imposed.Results Five studies were identified for critical appraisal using the CASP tools. These were a combination of systematic reviews and case series. Two case series were excluded due to low quality evidence. Curtin et al., Davis et al. and Constantinides et al. together with guidelines from the Scottish Dental Clinical Effectiveness Programme, have highlighted a protocol in managing these patients in a dental surgical setting.Conclusion Patients on novel anticoagulant therapy requiring dental surgery can be managed appropriately either without discontinuation of therapy or a delay in dose. For those patients at higher risks of postoperative bleeding complications, it is advised to liaise with the specialist physician.

Topics: Administration, Oral; Anticoagulants; Dabigatran; Humans; Oral Surgical Procedures; Postoperative Hemorrhage; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban

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

Cancer patients with venous thromboembolism (VTE) are at increased risk for both bleeding and VTE recurrence. Anticoagulation with low-molecular-weight heparin (LMWH) is the standard of care during the initial and long-term treatment phase (i.e. during the first 3 - 6 months of therapy) based on its overall beneficial safety and efficacy profile compared to vitamin K antagonists (VKAs). The direct oral anticoagulants (DOACs) rivaroxaban, apixaban, edoxaban, and dabigatran are approved for the treatment of acute VTE, and the combined six phase-3 trials have included > 1500 patients with active cancer, as defined by variable selection criteria. Subgroup analyses of these patients, either pooled or separately reported, suggest that DOACs could be a safe and efficacious alternative to VKA therapy for the treatment of cancer-associated VTE. However, the populations of cancer patients included in the DOAC and LMWH trials are not comparable with regard to mortality and VTE risk, and no specific data from direct head-to-head comparisons of DOACs with LMWHs are currently available. The use of DOACs for the management of VTE in cancer is thus not recommended by clinical practice guidelines.

Topics: Acute Disease; Administration, Oral; Anticoagulants; Clinical Trials, Phase III as Topic; Dabigatran; Guideline Adherence; Heparin, Low-Molecular-Weight; Humans; Long-Term Care; Neoplasms; Pyrazoles; Pyridines; Pyridones; Risk Factors; Rivaroxaban; Secondary Prevention; Thiazoles; Venous Thromboembolism

Venous thromboembolism causes significant morbidity and mortality in patients after total joint arthroplasty. Although network meta-analyses have demonstrated a benefit of various thromboprophylactic agents, there remains a concern in the surgical community regarding the resulting wound complications. There is currently no systematic review of the surgical site bleeding complications of thromboprophylactic agents. The aim of this study was to systematically review the surgical site bleeding outcomes of venous thromboembolism prophylaxis in this population.. A systematic review and meta-analysis was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Randomized controlled trials comparing more than one of low-molecular-weight heparin (LMWH), warfarin, rivaroxaban, apixaban, dabigatran, aspirin, or no pharmacologic treatment in patients after total hip or knee arthroplasty were selected for inclusion. Five meta-analyses were performed to compare LMWH with control, warfarin, apixaban, rivaroxaban, and dabigatran.. Forty-five randomized controlled trials of 56,730 patients were included. LMWH had a significantly increased relative risk of surgical site bleeding in comparison with control (relative risk, 2.32; 95% confidence interval, 1.40-3.85) and warfarin (1.54; 1.23-1.94). The relative risk of LMWH trended higher than apixaban (1.27; 1.00-1.63) and was similar to rivaroxaban (0.95; 0.74-1.23). Only 1 study reported the risk of surgical site bleeding in LMWH vs dabigatran (5.97; 2.08-17.11).. LMWH increased the risk of surgical site bleeding compared with control, warfarin. and dabigatran and trended toward an increased risk compared with apixaban. The risk of surgical site bleeding was similar with LMWH and rivaroxaban.

Topics: Anticoagulants; Arthroplasty; Arthroplasty, Replacement, Knee; Aspirin; Dabigatran; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Incidence; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Risk; Rivaroxaban; Treatment Outcome; Venous Thromboembolism; Warfarin

Topics: Administration, Oral; Anticoagulants; Dabigatran; Humans; Perioperative Period; Postoperative Complications; Pyrazoles; Pyridones; Rivaroxaban; Thromboembolism

To evaluate current clinical evidence for management of oral anticoagulation therapy after gastrointestinal bleeding (GIB) with an emphasis on whether to, when to, and how to resume an anticoagulation therapy.. Relevant articles from MEDLINE, Cochrane Library, and EMBASE databases were identified from 1946 through May 20, 2017, using the keywords: gastrointestinal hemorrhage or gastrointestinal bleeding and antithrombotic therapy or anticoagulation therapy or warfarin or dabigatran or rivaroxaban or apixaban or edoxaban.. All English-language studies assessing management of oral anticoagulation therapy after GIB were evaluated.. A total of 9 studies were identified. Four retrospective cohort studies showed that resuming anticoagulation therapy was associated with significantly lower rate of thromboembolism (TE) in the general population. Meta-analyses and prospective cohort studies also supported this finding. Two retrospective cohort studies indicated an increase in GIB when anticoagulation reinitiation occurred in less than 7 days without a decrease in TE. Resuming therapy between 7 and 15 days did not demonstrate a significant increase in GIB or TE. A large retrospective study showed that apixaban was associated with the significantly lowest risk of GIB compared with both rivaroxaban and dabigatran.. Anticoagulation therapy resumption is recommended, with resumption being considered between 7 and 14 days following GIB regardless of the therapy chosen. Data for warfarin management after GIB should be applied with caution to direct oral anticoagulants (DOACs) because of the quicker onset and experimental nature of reversal agents. Apixaban may be a preferred option when restarting a DOAC therapy.

Topics: Anticoagulants; Dabigatran; Gastrointestinal Hemorrhage; Humans; Pyrazoles; Pyridones; Rivaroxaban; Thromboembolism; 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

Direct oral anticoagulants (DOAC) are indicated for stroke prevention in atrial fibrillation and for the prevention and treatment of venous thromboembolism. As any anticoagulant, they are associated with a bleeding risk. Management of DOAC-induced bleeding is challenging. Idarucizumab, antidote for dabigatran, is currently available and is part of the therapeutic strategy, whereas antidotes for anti-Xa agents are under development. Activated or non-activated prothrombin concentrates are proposed, although their efficacy to reverse DOAC is uncertain. We propose an update on DOAC-associated bleeding management, integrating the availability of idarucizumab and the critical place of DOAC concentration measurements.

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Antidotes; Antithrombins; Arginine; Blood Coagulation Factors; Blood Transfusion; Dabigatran; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Hemostatics; Humans; Piperazines; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban; Stroke; Thrombophilia

It is unclear if the risk of intraocular bleeding with novel oral anticoagulants differs compared with warfarin.. To characterize the risk of intraocular bleeding with novel oral anticoagulants compared with warfarin.. A systematic review and meta-analysis was undertaken in an academic medical setting. MEDLINE and ClinicalTrials.gov were searched for randomized clinical trials published up until August 2016. This search was supplemented by manual bibliography searches of identified trials and other review articles.. Studies were eligible for inclusion if they were phase 3 randomized clinical trials, enrolled patients with atrial fibrillation or venous thromboembolism, compared a novel oral anticoagulant (dabigatran, rivaroxaban, apixaban, or edoxaban) with warfarin, and recorded event data on intraocular bleeding. Data on intraocular bleeding were pooled using inverse-variance, weighted, fixed-effects meta-analysis.. The PRISMA guidelines were used for abstracting data and assessing quality. Independent extraction was performed by 2 investigators.. Intraocular bleeding events and associated risk ratio for novel oral anticoagulants compared with warfarin.. Twelve trials investigating 102 627 patients were included. Randomization to novel oral anticoagulants was associated with a 22% relative reduction in intraocular bleeding compared with warfarin (risk ratio, 0.78; 95% CI, 0.61-0.99). There was no significant heterogeneity observed (I2 = 4.8%, P = .40). Comparably lower risks of intraocular bleeding with novel oral anticoagulants were seen in subgroup analyses, with no significant difference according to the indication for anticoagulation (P for heterogeneity = .49) or the novel oral anticoagulant type (P for heterogeneity = .15). Summary estimates did not differ materially when random-effects meta-analytic techniques were used.. These results suggest that novel oral anticoagulants reduce the risk of intraocular bleeding by approximately one-fifth compared with warfarin. Similar benefits were seen in both patients with atrial fibrillation and venous thromboembolism. Our data have particular relevance for patients at higher risk of spontaneous retinal and subretinal bleeding. These findings may also have important implications in the perioperative period, in which the use of novel oral anticoagulants may be superior. Future studies are required to better characterize the optimal management of patients with both ophthalmic disease and cardiovascular comorbidities requiring anticoagulation.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Eye Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Risk Assessment; Rivaroxaban; Thiazoles; Venous Thromboembolism; Warfarin

Evidence from the real-world setting complements evidence coming from randomized controlled trials. We aimed to summarize all available evidence from high-quality real-world observational studies about efficacy and safety of nonvitamin-K oral anticoagulants compared with vitamin-K antagonists in patients with atrial fibrillation.. We searched PubMed and Web of Science until January 7, 2017 for observational nationwide or health insurance databases reporting matched or adjusted results comparing nonvitamin-K oral anticoagulants versus vitamin-K antagonists in patients with atrial fibrillation. Outcomes assessed included ischemic stroke, ischemic stroke or systemic embolism, any stroke or systemic embolism, myocardial infarction, intracranial hemorrhage, major hemorrhage, gastrointestinal hemorrhage, and death.. In 28 included studies of dabigatran, rivaroxaban, and apixaban compared with vitamin-K antagonists, all 3 nonvitamin-K oral anticoagulants were associated with a large reduction of intracranial hemorrhage (apixaban hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.31-0.63; dabigatran HR, 0.42; 95% CI, 0.37-0.49; rivaroxaban HR, 0.64; 95% CI, 0.47-0.86); similar rates of ischemic stroke and ischemic stroke or systemic embolism (apixaban HR, 1.05; 95% CI, 0.75-1.19 and HR, 1.08; 95% CI, 0.95-1.22 / dabigatran HR, 0.96; 95% CI, 0.80-1.16 and HR, 1.17; 95% CI, 0.92-1.50 / rivaroxaban HR, 0.89; 95% CI, 0.76-1.04 and HR, 0.73; 95% CI, 0.52-1.04, respectively); apixaban and dabigatran with lower mortality (HR, 0.65; 95% CI, 0.56-0.75 and HR, 0.63; 95% CI, 0.53-0.75, respectively); apixaban with fewer gastrointestinal (HR, 0.63; 95% CI, 0.42-0.95) and major hemorrhages (HR, 0.55; 95% CI, 0.48-0.63); dabigatran and rivaroxaban with more gastrointestinal hemorrhages (HR, 1.20; 95% CI, 1.06-1.36 and HR, 1.24; 95% CI, 1.08-1.41, respectively); dabigatran and rivaroxaban with similar rate of myocardial infarction (HR, 0.96; 95% CI, 0.77-1.21 and HR, 1.02; 95% CI, 0.54-1.89, respectively).. This meta-analysis confirms the main findings of the randomized controlled trials of dabigatran, rivaroxaban, and apixaban in the real-world setting and, hence, strengthens their validity.

Topics: Anticoagulants; Atrial Fibrillation; Brain Ischemia; Dabigatran; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Myocardial Infarction; Proportional Hazards Models; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Warfarin

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

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

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

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

Anticoagulation in patients with impaired kidney function can be challenging since drugs' pharmacokinetics and bioavailability are altered in this setting. Patients with chronic kidney disease (CKD) treated with conventional anticoagulant agents [vitamin K antagonist (VKA), low-molecular weight heparin (LMWH) or unfractionated heparin (UFH)] are at high risk of bleeding events (both non-major and major clinically relevant bleeding). While anticoagulation reduces the risk of thromboembolic events, the co-existing bleeding risk and the fact that the most commonly used anticoagulation agents are eliminated via the kidneys pose additional challenges. More recently, two classes of direct oral anticoagulant agents (DOACs) have been investigated for the prevention and management of venous thromboembolic events: the direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban, and the direct thrombin inhibitor dabigatran. In this review, we discuss the complex challenges and the practical considerations associated with the management of anticoagulation treatment in patients with CKD, with a special focus on DOACs.

Topics: Administration, Oral; Anticoagulants; Dabigatran; Hemorrhage; Heparin; Humans; Pyrazoles; Pyridones; Renal Insufficiency, Chronic; Rivaroxaban; Thrombosis; Vitamin K

For more than half a century, warfarin, a vitamin K antagonist, has been the anticoagulant of choice. However, direct oral anticoagulants are rapidly gaining in popularity, which poses the need for efficacious reversal agents. This review article summarizes the strategies and agents used to reverse oral anticoagulants.

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

After arthroplasty treatment, some complications commonly occur, such as early revision, infection/dislocation, and venous thromboembolism (VTE). This study aims to use a network meta-analysis to compare effects of 9 anticoagulant drugs (edoxaban, dabigatan, apixaban, rivaroxaban, warfarin, heparin, bemiparin, ximelagatran, and enoxaparin) in preventing postoperative complications in arthroplasty patients.. After retrieving PubMed, Embase, and Cochrane Library database from the inception to November 2016, randomized controlled trials were enrolled. The integration of direct and indirect evidences was performed to calculate odd ratios and the surface under the cumulative ranking curves. Nineteen eligible randomized controlled trials were included.. The network meta-analysis results showed that compared with warfarin, edoxaban, apixaban, and rivaroxaban had a lower incidence rate in asymptomatic deep venous thrombosis, which indicated that edoxaban, apixaban, and rivaroxaban had better effects on prevention. Similarly, in comparison to enoxaparin, edoxaban and rivaroxaban had better effect; rivaroxaban was better than ximelagatran in preventive effects. Compared with apixaban, edoxaban, dabigatan, rivaroxaban, and enoxaparin had a higher incidence rate in clinically relevant non-major bleeding, which showed that preventive effects were relatively poor. In addition, the results of the surface under the cumulative ranking curves showed that rivaroxaban and bemiparin worked best on symptomatic deep venous thrombosis and pulmonary embolism. In terms of bleeding, apixaban and warfarin had better preventive effects.. Our findings suggested that rivaroxaban may work better in terms of symptomatic deep venous thrombosis and pulmonary embolism, whereas apixaban had better preventive effects in bleeding.

Topics: Anticoagulants; Arthroplasty; Azetidines; Benzylamines; Dabigatran; Enoxaparin; Heparin; Heparin, Low-Molecular-Weight; Humans; Network Meta-Analysis; Postoperative Complications; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Treatment Outcome; Venous Thromboembolism; 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

Enzalutamide, a novel, oral androgen receptor antagonist used for the treatment of metastatic, castration-resistant prostate cancer, has been shown to improve overall and progression-free survival, prolong time to initiation of chemotherapy, reduce skeletal-related events, and carry a favorable adverse effect profile. Metastatic prostate cancer is a disease of older men, a population with an increased incidence of medical comorbidities warranting anticoagulation. Prostate cancer itself, along with some of its therapies, is also prothrombotic. Enzalutamide interacts with several anticoagulants through various mechanisms, making their concurrent use clinically challenging. As such, complex decisions about anticoagulation in these patients are frequently encountered by treating physicians. In this review, we describe the potential interactions between enzalutamide and various anticoagulants, and suggest management paradigms based on the current body of knowledge for patients with atrial fibrillation, venous thromboembolism, and mechanical heart valves.

Topics: Androgen Receptor Antagonists; Anticoagulants; Atrial Fibrillation; Benzamides; Dabigatran; Drug Interactions; Embolism; Heart Valve Prosthesis; Heparin, Low-Molecular-Weight; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Venous Thromboembolism; Warfarin

Recent findings require an update of previous recommendations for the perioperative use of Direct Oral AntiCoagulants (DOACs). A break in preoperative treatment of 24-96 hours is recommended based on the pharmacokinetic profiles of DOACs and depends on individual patient characteristics, their renal and possibly liver function, and their surgery-related risk of bleeding. In cases of renal or hepatic insufficiency, whether to extend the preoperative interruption of IIa- and Xa-inhibitors is a clinical decision that must be reached on an individual patient basis. In cases of epidural or spinal anaesthesia, more conservative pausing-intervals are recommended due to the risk of persistent neurologic deficits (e.g., paraplegia) following the development of spinal subdural and epidural haematomas. Elective surgery should be postponed according to these recommendations. Preoperative "bridging" with LMWH (more precisely referred to as "switching") should be omitted due to a significantly increased risk of bleeding. In addition, the incidence of perioperative thromboembolic risks, such as DVT, PE, and stroke, are no different whether interruption or "switching" is undertaken. Postoperatively, the DOACs can be reinstituted within the first 24 hours. In cases of major surgery or if there is a higher risk of bleeding, resumption of DOACS should only begin after 24-72 hours. In patients with an elevated thromboembolic risk, transient postoperative LMWH administration can be recommended during this period.Interaction of DOACs with other drugs usually occurs during the absorption, transport and elimination of these drugs. Therefore, substance- specific restrictions and recommendations should be observed during these times. In everyday clinical practice, webbased, independent information portals on drug-interactions are very helpful in providing safe and rapid information about potential interactions when DOACs are used in combination with other drugs, especially during perioperative management.Non-adherence to medications is a worldwide problem that has dangerous and costly consequences. Present data suggest that persistence is the primary factor that supports adherence. Despite the adherence data presented in the DOACS approval studies (e.g., persistence in the treatment of acute venous thromboembolism has been reported to be between 94-99%), the first registries and meta-analyses provide sobering results regarding the incidence of persistence and the success rate of i. Aktuelle Erkenntnisse erfordern die Aktualisierung früherer Empfehlungen zum perioperativen Einsatz von direkte orale Antikoagulanzien (DOAKs). Auf Grundlage der pharmakokinetischen Profile wird in Abhängigkeit von Nierenfunktion, ggf. Leberfunktion sowie individuellem und eingriffsspezifischem Blutungsrisiko eine präoperative Pausierung von 24–96 Stunden in Abhängigkeit von dem verwendeten DOAK empfohlen. Bei schwerer Nieren- oder Leberinsuffizienz ist es eine individuelle, klinische Entscheidung, die präoperative Pause für die Xa-inhibitoren zu verlängern. Für Patienten mit rückenmarksnahen Regionalanästhesieverfahren gelten aufgrund des Risikos von spinal sub- und epiduralen Hämatomen und dem Risiko bleibender schwerer neurologischer Defizite (Querschnittslähmung) sehr konservative Intervalle im oberen Pausierungsbereich. Ein bereits präoperativ beginnendes „Bridging” mit NMH (eigentlich „Switching”) sollte wegen signifikant erhöhter Blutungsrisiken unterbleiben. Das perioperative Thromboembolierisiko (z.B. Thrombose, Lungenembolie, Hirninfarkt) ist nach einer präoperativen Pause bzw. einem präoperativen „Switching” nicht unterschiedlich. Postoperativ können DOAKs innerhalb von 24 h, nach größeren Eingriffen bzw. höherem Blutungsrisiko erst nach 24–72 Stunden wiederaufgenommen werden. Eine postoperative, passagere Umstellung auf eine NMH-Gabe („Switching”) bei erhöhtem venösem Thromboembolierisiko kann in diesem Zeitraum erfolgen.Medikamenteninteraktionen von direkten oralen Antikoagulanzien treten meist bei der Absorption, beim Transport und bei der Elimination von anderen Medikamenten auf. Hierbei sind substanzspezifische Einschränkungen und Empfehlungen zu beachten. Um im klinischen Alltag eine sichere und schnelle Information, auch über DOAKs in Kombination mit anderen Medikamenten im perioperativen Management, zu erhalten, sind webbasierte, unabhängige Informationsportale sehr hilfreich.Die Non-Adhärenz von Medikamenten ist weltweit verbreitet, ist gefährlich und teuer in ihren Folgen. Die aktuellen Daten beschreiben vorwiegend die Persistenz als ein orientierendes Maß für die Adhärenz. Unabhängig von den Zulassungsstudien der DOAKs (Persistenz bei der Therapie akuter venöser Thromboembolien zwischen 94 – 99%) liefern erste Register und Metaanalysen ernüchternde Ergebnisse zur Persistenz und zur Verbesserung der Adhärenz der DOAKs in der Langzeitanwendung.

Topics: Administration, Oral; Anticoagulants; Dabigatran; Drug Interactions; Drug Substitution; Heparin, Low-Molecular-Weight; Humans; Kidney Function Tests; Liver Function Tests; Metabolic Clearance Rate; Perioperative Care; Pyrazoles; Pyridines; Pyridones; Risk Factors; Rivaroxaban; Thiazoles; Venous Thromboembolism

New oral anticoagulants (NOACs) are likely to have a major impact in the next few years, changing clinical practice of anticoagulation therapy. Evidence on its efficacy and superiority to vitamin K antagonists (VKAs) in treating non-cancer patients have been reported in a few clinical trials. However, patients with cancer are complicated by the prothrombotic nature of the disease, need for potentially invasive surgery and interventions, and altered drug handling. This chapter examines the available evidence and guidelines on the use of NOAC in patients with cancer.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Catheters, Indwelling; Dabigatran; Drug Administration Schedule; Drug Dosage Calculations; Humans; Neoplasms; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiazoles; Venous Thromboembolism; Venous Thrombosis

Pulmonary embolism (PE) affects >600,000 patients per year in the United States. Evaluation includes clinical decision rules, laboratory tests, and several imaging modalities. The diagnosis of PE has risen in recent years, particularly subsegmental PE (SSPE). Controversy exists concerning the diagnosis and treatment of these lesions.. We sought to provide emergency physicians with a review of the controversies surrounding PE testing and the diagnosis and treatment of SSPE.. With the rise of computed tomography (CT) testing for PE, diagnosis has increased. Providers often omit risk stratification in favor of D-dimer or imaging, which does not have literature support. The detection of PE has risen by 80%, and this increased testing is associated with several risks, including contrast reaction, nephropathy, and increased radiation. SSPE diagnosis has risen with improved imaging technology, but the literature shows low interobserver agreement with diagnosis of true SSPE. Studies disagree on the clinical significance and dangers of this PE subset. The American College of Chest Physicians 2016 guidelines recommend withholding anticoagulation for SSPE with low risk for recurrent thrombus and no concurrent deep vein thrombosis. Patients at high risk for recurrent venous thromboembolism or with deep vein thrombosis warrant anticoagulation. The provider is ultimately responsible for appropriate evaluation with risk stratification and selective testing.. SSPE presents a quandary, because the literature differs in showing harm despite increased diagnosis. American College of Chest Physicians guidelines for the treatment of SSPE take into account the patient, the imaging, and other imaging modalities. Providers should use risk stratification with shared decision-making in the evaluation and treatment of SSPE.

Topics: Anticoagulants; Dabigatran; Decision Making; Humans; Patient Outcome Assessment; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Risk Factors; Rivaroxaban; Thiazoles; Tomography, X-Ray Computed; Venous Thromboembolism

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 and potentially fatal complication of arthroplasty.. We reviewed randomized trials to determine which anticoagulant has the best safety and efficacy in hip and knee arthroplasty patients. We searched PubMed, MEDLINE, and EMBASE through January 2016.. Compared to enoxaparin (most commonly dosed 40 mg once daily), the relative risk (RR) of VTE was lowest for edoxaban 30 mg once daily (0.49; 95% confidence interval [CI], 0.32-0.75), fondaparinux 2.5 mg once daily (0.53; 95% CI, 0.45-0.63), and rivaroxaban 10 mg once daily (0.55; 95% CI, 0.46-0.66), and highest for dabigatran 150 mg once daily (1.19; 95% CI; 0.98-1.44). The RR of major/clinically relevant bleeding was lowest for apixaban 2.5 mg twice daily (0.84; 95% CI; 0.70-0.99) and highest for rivaroxaban (1.27; 95% CI, 1.01-1.59) and fondaparinux (1.64; 95% CI, 0.24-11.35). Fondaparinux was the only agent that was more effective than enoxaparin 30 mg twice daily (VTE RR = 0.58; 95% CI, 0.43-0.76).. With the possible exception of apixaban, newer anticoagulants that lower the risk of postoperative VTE increase bleeding.

Topics: Anticoagulants; Arthroplasty, Replacement, Knee; Dabigatran; Enoxaparin; Fondaparinux; Hemorrhage; Humans; Morpholines; Polysaccharides; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism

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

Many patients under oral anticoagulation therapy need percutaneous or surgical interventions/operations. For vitamin K antagonists (VKA), there are recommendations regarding preoperative or postoperative administration. Management of the new oral anticoagulants (NOAC) was supposed to be easier - but some aspects must be considered. Due to the different pharmacokinetic profiles of substances such as dabigatran, rivaroxaban, apixaban, and edoxaban, different recommendations are given.Upon periprocedural management, thromboembolic risk has to be considered in patients treated with NOACs. NOACS have a pharmacokinetic advantage in terms of a rapid onset and rapid elimination via the liver and kidneys. Impaired renal function results in extended half-life of NOACs considerably.Surgical procedures under NOACS can be scheduled at the beginning of next dosing interval or omitted in low/minimal bleeding risk patients, so that only 2-3 NOAC doses are not administered. In patients with moderate and high risk of bleeding, there should be a NOAC break of 24-48 h prior to surgery in order to allow a corresponding decay of the active metabolite. In patients with low/intermediate risk for thromboembolism, no bridging is necessary if the "unprotected" time (NOAC break) is less than 4-5-(7) days. In patients at high risk of thromboembolism, individual consideration must be taken regarding bridging or extended NOAC break. Whether NOACs can be dispensed or bridging is necessary in these patients must be clarified in randomized trials for periprocedural management of NOACs patients.

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Anticoagulants; Blood Loss, Surgical; Dabigatran; Drug Interactions; Half-Life; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Surgical Procedures, Operative; Thiazoles; Thromboembolism; Vitamin K

The non-vitamin K antagonists (NOAC) are an integral component of our antithrombotic prevention and therapy. For four of the NOAC, their non-inferiority or even superiority versus vitamin K antagonists (VKA) has been proven. Thus, the management of special patient cohorts or the management of active bleeding complications is a focus of current discussion.In addition to prospective trials, numerous retrospective analyses of health insurers or public health provider data have been analyzed and published as "real life" or "real-world evidence" data. In almost all data sets the results of the NOAC approval trials were confirmed, demonstrating their non-inferiority or even superiority versus VKA. Attempts to compare the various NOAC with each other must be viewed critically since the real-world evidence (RWE) analysis provides very divergent results depending on the cohorts analyzed. Thus, a substantial prescriber-bias must be taken into account and never be excluded.In order to improve the management of bleeding complications, NOAC antidotes were developed. While the factors Xa antidote, andexanet alpha, a modified coagulation factor deleted of an intrinsic activity, will not be available before 2018, the dabigatran antidote idarucizumab is already in clinical use. Idarucizumab, a monoclonal antibody fragment directed against dabigatran, is able to completely antagonize the effect of dabigatran within minutes. Therefore, the drug has the potential to terminate life-threatening bleeding complications earlier and make emergency surgical or interventional procedures possible without an elevated bleeding risk.

Topics: Aged; Antibodies, Monoclonal, Humanized; Anticoagulants; Antidotes; Dabigatran; Factor Xa; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban; Stroke; Thromboembolism; Vitamin K; Warfarin

Approximately 900,000 people are affected by some sort of venous thromboembolic (VTE) event every year in the United States. VTE diagnosis used to mean treatment with medications that required routine lab monitoring for safety and efficacy. Activated factor X (FXa) inhibition has emerged as a convenient pathway for management of VTE and currently three FXa inhibitors are available for anticoagulation management - rivaroxaban, apixaban, and edoxaban. Continued development of medications utilizing this pathway may offer advantages via novel pharmacokinetic or pharmacodynamic properties that may minimize the adverse effects associated with traditional anticoagulant therapy. This review summarizes the available information regarding pharmacokinetic, pharmacodynamic, and early safety and efficacy data for three factor Xa inhibitors being developed - darexaban, betrixaban and nokxaban. The studies reviewed in this article suggests that three newer agents possess the potential for promise based on early phase I and II trials.

Topics: Administration, Oral; Animals; Azepines; Benzamides; Blood Coagulation; Drug Discovery; Factor Xa Inhibitors; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Venous Thromboembolism

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

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

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

Direct oral anticoagulants (DOACs), including the direct thrombin inhibitor, dabigatran, and the direct factor Xa (FXa) inhibitors, rivaroxaban, apixaban and edoxaban, are approved for thromboembolism prevention and treatment. These drugs do not require routine coagulation monitoring but, in some circumstances, measurement of drug level or anticoagulant effect may be necessary. Although traditional coagulation tests lack analytical sensitivity and specificity, they are widely available and inexpensive, and can provide useful information regarding the residual anticoagulant effect of DOACs. Hemoclot® and ecarin-based assays can be used to quantify dabigatran level and calibrated chromogenic anti-FXa assays are suitable for measuring rivaroxaban, apixaban and edoxaban levels, but these tests are not yet widely available.

Topics: Administration, Oral; Anticoagulants; Blood Coagulation; Blood Coagulation Tests; Chromatography, High Pressure Liquid; Dabigatran; Drug Monitoring; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles

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

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

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

Direct oral anticoagulant (DOAC) drugs (dabigatran, rivaroxaban, and apixaban) have emerged in the last decade to overcome some of the drawbacks of existing medications. To date, little is known about the dental management of patients taking these drugs. This study was undertaken to establish the evidence for the management of patients undergoing dental procedures while taking these medications. A rapid review approach was used to identify clinical and scientific research related to dental surgery performed in patients taking DOACs in order to produce an evidence summary. The rapid review did not identify any systematic reviews or original clinical trials and the overall quality of evidence found was poor. Most of the literature consisted of non-structured review articles and guidance documents based on assumptions from non-dental data and expert opinion, and recommendations on best practice varied throughout. The findings from the review of the literature varied considerably. Currently, recommendations are based on poor quality scientific data and clinical trials are required to establish best evidence-based practice guidance.

Topics: Administration, Oral; Antithrombins; Dabigatran; Factor Xa Inhibitors; Humans; Oral Surgical Procedures; Pyrazoles; Pyridones; Rivaroxaban

The introduction of direct oral anticoagulant (DOAC) therapy into clinical use in the past 5 years has had significant impact on the clinical laboratory. Clinicians' desire to determine plasma drug presence or measure drug concentration, and more recent observations regarding the limitations and utility of coagulation testing in the setting of DOAC treatment, suggest that early published recommendations regarding laboratory testing should be reassessed. These initial recommendations, furthermore, were often based on drug-spiked plasma studies, rather than samples from patients receiving DOAC therapy. We have demonstrated that reagent sensitivity varies significantly whether drug-spiked samples or samples from DOAC-treated patients are tested. Data from drug-enriched samples must therefore be interpreted with caution or be used as a guide only. We present laboratory assays that can be used to determine drug presence and to measure drug concentration, and provide recommended testing algorithms. As DOAC therapy may significantly impact on specialty coagulation assays, we review those tests with the potential to give false-positive and false-negative results.

Topics: Administration, Oral; Algorithms; Anticoagulants; Antithrombins; Blood Coagulation; Blood Coagulation Tests; Calibration; Chemistry, Clinical; Dabigatran; Dose-Response Relationship, Drug; Humans; Partial Thromboplastin Time; Prothrombin Time; Pyrazoles; Pyridones; Rivaroxaban

Anticoagulation in catheter ablation (CA) of atrial fibrillation (AF) is of paramount importance for prevention of thromboembolic events, and recent studies favor uninterrupted vitamin K antagonists (VKAs). We aimed to compare the efficacy and safety of new oral anticoagulants (NOACs) to uninterrupted VKAs for anticoagulation in CA by performing a meta-analysis. PubMed, EMBASE, the Cochrane Library, and Clinicaltrials.gov databases were searched for studies comparing NOACs with uninterrupted VKAs in patients who underwent CA for AF from January 1, 2000, to August 31, 2015. Odds ratio (OR) and Peto's OR (POR) were used to report for event rates >1% and <1%, respectively. A total of 11,686 patients with AF who underwent CA in 25 studies were included in this analysis. There was no significant difference between NOACs and uninterrupted VKAs in occurrence of stroke or transient ischemic attacks (POR 1.35, 95% CI 0.62 to 2.94) and major bleeding (POR 0.87, 95% CI 0.58 to 1.31), which were consistent in subgroup analysis of interrupted and uninterrupted NOACs. A lower risk of minor bleeding was observed with NOACs (OR 0.80, 95% CI 0.65 to 1.00), and no major differences were observed for the risk of thromboembolic events, cardiac tamponade or pericardial effusion requiring drainage, and groin hematoma. NOACs, whether interrupted preprocedure or not, were associated with equal rates of stroke or TIA and major bleeding complications and less risk of minor bleeding compared with uninterrupted VKAs in CA for AF.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Catheter Ablation; Dabigatran; Factor Xa Inhibitors; Humans; Ischemic Attack, Transient; Observational Studies as Topic; Prothrombin; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Time Factors; Treatment Outcome; Vitamin K; Warfarin

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

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

The use of non-vitamin K antagonist oral anticoagulants (NOACs) has become a breakthrough in anticoagulant treatment and it is expected to rise significantly in upcoming years. The use of conventional anticoagulants have several limitations: subcutaneous administration of heparin, or close monitoring of INR during application of vitamin K antagonists. In the last decade, target-specific oral anticoagulants (TSOAC) including dabigatran, rivaroxaban, apixaban, edoxaban have been marketed for prophylaxis and treatment. Therefore, it is crucial to understand the potential uses, side effects, and management of these agents in routine practice. NOACs have major pharmacologic advantages, including a rapid onset and offset of action, fewer drug interactions than conventional anticoagulants, and predictable pharmacokinetics. These agents are gaining popularity among both physicians and patients because of their easiness of administration and the eliminating the requirement for regular coagulation monitoring. In this review, we focus on discussing practical recommendations for the use of NOACs and the risks and benefits of incorporating them into routine practice.

Topics: Administration, Oral; Anticoagulants; Dabigatran; Humans; Practice Patterns, Physicians'; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles

To review clinical data on direct oral anticoagulants (DOACs) used in the acute treatment of venous thromboembolism (VTE) as well as practical considerations when using these products.. Searches of PubMed and Google Scholar for VTE, deep vein thrombosis, pulmonary embolism, and relevant drug international nonproprietary names were conducted. Additional online searches were conducted for prescribing information.. Relevant articles on dabigatran, rivaroxaban, apixaban, and edoxaban for the management of VTE compared with oral vitamin K antagonists (VKAs; published between 1966 and December 2015) were reviewed and summarized, together with information on dosing, pharmacokinetics/pharmacodynamics, and drug-drug interactions.. The DOACs have the potential to circumvent many of the disadvantages of VKAs. At a minimum, they greatly increase the available therapeutic options, thus providing a greater opportunity for clinicians to select a management option that best fits the needs of individual patients. Despite the significant advance that DOACs represent, they are not without risk and require careful consideration of a number of clinical issues to optimize safety and efficacy.. The emergence of DOACs for the management of thromboembolic disorders represents a paradigm shift from oral VKAs. The DOACs provide similar efficacy and improved safety in selected patients as compared with VKAs. Clinicians treating VTE need to be familiar with the intricacies involved in using these agents, including the appropriate dose selection for the relevant indication, avoidance of drug-drug and drug-disease interactions, and consideration of dose adjustments in specific clinical situations, such as organ dysfunction.

Topics: Administration, Oral; Anticoagulants; Dabigatran; Drug Interactions; Humans; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiazoles; Treatment Outcome; Venous Thromboembolism; Venous Thrombosis

To assess the cost-effectiveness of apixaban versus rivaroxaban, low-molecular-weight heparin (LMWH)/dabigatran, and LMWH/vitamin K antagonist (VKA) for the initial treatment and prevention of recurrent thromboembolic events in patients with venous thromboembolism (VTE).. A Markov model was developed to evaluate the pharmacoeconomic effect of 6 months of treatment with apixaban versus other anticoagulants over a lifetime horizon. Network meta-analyses were conducted using the results of the Apixaban after the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis with First-Line Therapy (AMPLIFY), EINSTEIN-pooled, and RE-COVER I and II trials for the following end points: recurrent VTE, major bleeds, clinically relevant non-major bleeds, and treatment discontinuations. The analysis was conducted from the perspective of the United Kingdom National Health Service. The outcomes evaluated were the number of events avoided in a 1000-patient cohort, total costs, life years, quality-adjusted life years (QALYs), and cost per QALY gained over a patient's lifetime.. Treatment for 6 months with apixaban was projected to result in fewer recurrent VTE and bleeding events in comparison to rivaroxaban, LMWH/dabigatran, and LMWH/VKA. Apixaban was cost-effective compared with LMWH/VKA at an incremental cost-effectiveness ratio of £2520 per QALY gained and was a dominant (ie, lower costs and higher QALYs) alternative to either rivaroxaban or LMWH/dabigatran. Sensitivity analysis indicated that results were robust over a wide range of inputs.. The assessment of the effects and costs of apixaban in this study predicted that apixaban is a dominant alternative to rivaroxaban and LMWH/dabigatran and a cost-effective alternative to LMWH/VKA for 6 months of treatment of VTE and the prevention of recurrence.

Topics: Anticoagulants; Cost-Benefit Analysis; Dabigatran; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Recurrence; Rivaroxaban; Secondary Prevention; United Kingdom; Venous Thromboembolism

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

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

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

Direct oral anticoagulants are being presented as alternatives to warfarin for preventing stroke in patients with atrial fibrillation. Yet direct comparative trials between these agents in prevention of acute limb ischemia (ALI) are unavailable so far.. To conduct an adjusted indirect comparison meta-analysis between direct oral agents for prevention of acute limb ischemia in atrial fibrillation.. We conducted a systematic literature review searching electronic databases (MEDLINE and Embase) and the Cochrane Library from January 1990 through November 2014. Two blinded investigators reviewed all potentially relevant articles in a parallel manner by using a priori defined criteria. To assess the long-term efficacy and safety of these agents, only randomized clinical trials (RCTs) with follow-up durations of >1 year were included. The primary efficacy outcome was the end point of acute limb ischemia and/or extremity embolism.. A total of 44,563 patients from three RCTs met criteria for inclusion. Patients randomized to direct oral anticoagulants had a non-significant decreased risk for acute limb ischemia (risk ratio [RR]: 0.57, 95% confidence interval [CI]: 0.26-1.2). In the analysis between agents, however, rivaroxaban significantly lowered the risk of ALI compared to warfarin (RR: 0.23, 95% CI: 0.064-0.82), apixaban (RR: 0.26, 95% CI: 0.081-0.83), and dabigatran (RR: 0.24, 95% CI: 0.077-0.83).. Significant differences in prevention of acute limb ischemia may exist between oral anticoagulant agents in patients with atrial fibrillation. Rivaroxaban lowers the risk of limb embolism versus warfarin, apixaban and dabigatran.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Embolism; Humans; Ischemia; Leg; Odds Ratio; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Warfarin

Until recently, vitamin K antagonists (VKAs) were the only available oral anticoagulants evaluated for long-term treatment of patients with coronary heart disease (CHD), particularly after an acute coronary syndrome (ACS). Despite efficacy in this setting, VKAs are rarely used because they are cumbersome to administer. Instead, the more readily manageable antiplatelet agents are the mainstay of prevention in ACS patients. This situation has the potential to change with the introduction of non-VKA oral anticoagulants (NOACs), which are easier to administer than VKAs because they can be given in fixed doses without routine coagulation monitoring. The NOACs include dabigatran, which inhibits thrombin, and apixaban, rivaroxaban and edoxaban, which inhibit factor Xa. Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischaemia in ACS patients, most of whom were also receiving dual antiplatelet therapy with aspirin and clopidogrel. Although at the doses tested rivaroxaban was effective and apixaban was not, both agents increased major bleeding. The role for the NOACs in ACS management, although promising, is therefore complicated, because it is uncertain how they compare with newer antiplatelet agents, such as prasugrel, ticagrelor or vorapaxar, and because their safety in combination with these other drugs is unknown. Ongoing studies are also now evaluating the use of NOACs in non-valvular atrial fibrillation patients, where their role is established, with coexistent ACS or coronary stenting. Focusing on CHD, we review the results of clinical trials with the NOACs and provide a perspective on their future incorporation into clinical practice.

Topics: Administration, Oral; Animals; Anticoagulants; Clinical Trials as Topic; Coronary Artery Disease; Dabigatran; Drug Interactions; Humans; Platelet Aggregation Inhibitors; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles

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

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

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

The aim of this network meta-analysis was to evaluate the comparative efficacy and safety of dabigatran, rivaroxaban, apixaban, interrupted vitamin K antagonist (I-VKA), and continuous VKA (C-VKA) in patients undergoing radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF).. PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were searched to identify clinical trials comparing dabigatran, rivaroxaban, or apixaban with I-VKA or C-VKA, or against each other, in AF patients undergoing RFCA. A network meta-analysis was conducted to directly and indirectly compare the efficacy and safety of competitive anticoagulation regimens with a Bayesian random-effects model.. A total of 39 studies enrolling 27,766 patients were included. C-VKA demonstrated significant superiority over I-VKA in reducing thromboembolic events (risk difference [RD] -0.0068, 95 % confidence interval [CI] -0.0106 to -0.0032) and major bleeding complications (RD -0.0044, 95 % CI -0.0098 to -0.0006). Rivaroxaban compared with I-VKA was associated with a lower risk of thromboembolism (RD -0.0073, 95 % CI -0.0134 to -0.0012), being at the best ranking position among all of the compared anticoagulation regimens in terms of both the efficacy and safety. None of the remaining comparisons reached statistically significant difference in the rate of thromboembolism or major bleeding.. The present study suggests that C-VKA is superior to I-VKA for AF patients undergoing RFCA. Rivaroxaban is the highest probability to be the optimal alternative to C-VKA among the three non-VKA oral anticoagulants in AF ablation.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Catheter Ablation; Causality; Comorbidity; Dabigatran; Female; Humans; Incidence; Male; Middle Aged; Postoperative Complications; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Thromboembolism; Treatment Outcome; Vitamin K

Novel oral anticoagulants (NOACs) have emerged as a good alternative to warfarin in the prevention of stroke for patients with atrial fibrillation. NOAC use is increasing rapidly; therefore, greater understanding of their use in the perioperative period is important for optimal care. Studies and reviews that reported on the use of NOACs were identified, with particular focus on the perioperative period. PubMed was searched for relevant articles published between January 2000 and August 2015. The inevitable rise in the use of NOACs such as rivaroxaban (Xarelto™), apixaban (Eliquis™), edoxaban (Lixiana™) and dabigatran (Pradaxa™) may present a simplified approach to perioperative anticoagulant management due to fewer drug interactions, rapidity of onset of action and relatively short half-lives. Coagulation status, however, cannot reliably be monitored and no antidotes are currently available. When planning for discontinuation of NOACs, special consideration of renal function is required. Advice regarding the management of bleeding complications is provided for consideration in emergency surgery. In extreme circumstances, haemodialysis may be considered for bleeding with the use of dabigatran. NOACs will increasingly affect operative planning in plastic surgery. In order to reduce the incidence of complications associated with anticoagulation, the management of NOACs in the perioperative period requires knowledge of the time of last dose, renal function and the bleeding risk of the planned procedure. Consideration of these factors will allow appropriate interpretation of the current guidelines.

Topics: Administration, Oral; Algorithms; Anticoagulants; Dabigatran; Elective Surgical Procedures; Emergencies; Humans; Kidney; Liver; Perioperative Care; Plastic Surgery Procedures; Postoperative Hemorrhage; Practice Guidelines as Topic; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles

Topics: Administration, Oral; Anticoagulants; Dabigatran; Drug Interactions; Humans; Outpatients; Pyrazoles; Pyridines; Pyridones; Renal Insufficiency, Chronic; Rivaroxaban; Thiazoles; 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

Direct oral anticoagulants (DOACs) are establishing themselves as principle choices for the treatment of a variety of thrombotic disorders. DOACs are also known to affect common coagulation tests which are routinely performed for patients in clinical practice. An understanding of their varied effects is crucial for the appropriate ordering of coagulation tests and their interpretation.. Laboratories in public and private healthcare institutions and commercial sectors were surveyed on coagulation tests offered and their methods. A Medline and bibliography search, including a search on search engines, was performed for publications reporting the effects of dabigatran, apixaban and rivaroxaban on these coagulation tests. These papers were reviewed and summarised for consensus recommendations.. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are variably affected by the DOACs and dependent of the coagulation assays used. Clinicians must know which laboratory has performed these tests to logically interpret test results. A normal PT or aPTT does not exclude the presence of residual DOACs effect. The thrombin time is sensitive to dabigatran but not apixaban or rivaroxaban. Specialised coagulation tests such as thrombophilia tests are also variably affected by the DOACs. All laboratories in Singapore however, employ similar test methods permitting a common set of recommendations for specialised coagulation testing.. Knowledge of the effects of DOACs on coagulation testing is essential to determine the appropriateness of performing such tests and interpreting them coherently. Practical recommendations which are tests and location-specific are set out in this paper.

Topics: Antithrombins; Blood Coagulation Tests; Dabigatran; Factor Xa Inhibitors; Humans; Partial Thromboplastin Time; Practice Guidelines as Topic; Prothrombin Time; Pyrazoles; Pyridones; Rivaroxaban; Singapore

Topics: Anticoagulants; Dabigatran; Humans; Postoperative Complications; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Surgical Procedures, Operative

Worldwide, venous thromboembolism (VTE) is among the leading causes of death from cardiovascular disease, surpassed only by acute myocardial infarction and stroke. The spectrum of VTE presentations ranges, by degree of severity, from deep vein thrombosis to acute pulmonary thromboembolism. Treatment is based on full anticoagulation of the patients. For many decades, it has been known that anticoagulation directly affects the mortality associated with VTE. Until the beginning of this century, anticoagulant therapy was based on the use of unfractionated or low-molecular-weight heparin and vitamin K antagonists, warfarin in particular. Over the past decades, new classes of anticoagulants have been developed, such as factor Xa inhibitors and direct thrombin inhibitors, which significantly changed the therapeutic arsenal against VTE, due to their efficacy and safety when compared with the conventional treatment. The focus of this review was on evaluating the role of these new anticoagulants in this clinical context.

Topics: Anticoagulants; Dabigatran; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Time Factors; Venous Thromboembolism; Warfarin

Novel oral anticoagulants (NOACs) such as dabigatran, rivaroxaban, apixaban and edoxaban have gained a lot of popularity as alternatives to warfarin for anticoagulation in various clinical settings. However, there is conflicting opinion regarding the absolute benefit of NOAC use in elderly patients. Low body mass, altered body composition of fat and muscle, renal impairment and concurrent presence of multiple comorbidities predispose elderly patients to many adverse effects with NOACs that are typically not seen in younger patients. There have been reports that NOAC use, in particular dabigatran, is associated with a higher risk of gastrointestinal bleeding in the elderly. Diagnosis and management of NOAC-associated bleeding in the elderly is difficult due to the absence of commonly available drug-specific antidotes that can rapidly reverse the anticoagulant effects. Moreover, in elderly patients, a number of factors such as the presence of other comorbid medical conditions, renal insufficiency, drug interactions from polypharmacy, risk of falls and dementia need to be considered before prescribing anticoagulation therapy. Elderly patients frequently have compromised renal function, and therefore dose adjustments according to creatinine clearance for NOACs need to be made. As each NOAC comes with its own unique advantages and safety profile, an individualized case by case approach should be adopted to decide on the appropriate anticoagulation regimen for elderly patients after weighing the overall risks and benefits of therapy.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Hemorrhage; Humans; Meta-Analysis as Topic; Precision Medicine; Pyrazoles; Pyridones; Risk; Rivaroxaban; Stroke; Warfarin

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

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

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

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

Half of all patients with acute venous thromboembolism are aged over 70 years; they then face the added hazard of an age-related increase in the incidence of major bleeding. This makes it even more important to weigh the balance of benefit and risk when considering anticoagulant treatment and treatment duration. Traditional treatment with a heparin (usually low molecular weight) followed by a vitamin K antagonist such as warfarin is effective but is often complicated, especially in the elderly. The direct-acting oral anticoagulants (DOACs), i.e. the thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban, apixaban and edoxaban, are given in fixed doses, do not need laboratory monitoring, have fewer drug-drug interactions and are therefore much easier to take. Randomised trials, their meta-analyses and 'real-world' data indicate the DOACs are no less effective than warfarin (are non-inferior) and probably cause less major bleeding (especially intracranial). It seems the relative safety of DOACs extends to age above 65 or 70 years, although bleeding becomes more likely regardless of the chosen anticoagulant. Renal impairment, comorbidities (especially cancer) and interventions are special hazards. Ways to minimise bleeding include patient selection and follow-up, education about venous thromboembolism, anticoagulants, drug interactions, regular checks on adherence and avoiding needlessly prolonged treatment. The relatively short circulating half-lives of DOACs mean that time, local measures and supportive care are the main response to major bleeding. They also simplify the management of invasive interventions. An antidote for dabigatran, idarucizumab, was recently approved by regulators, and a general antidote for factor Xa inhibitors is in advanced development.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Clinical Trials as Topic; Dabigatran; Drug Interactions; Factor Xa Inhibitors; Hemorrhage; Humans; Practice Guidelines as Topic; Pyrazoles; Pyridones; Rivaroxaban; Venous Thromboembolism; Warfarin

Non-vitamin K oral anticoagulants (NOACs) are proven alternatives to vitamin K antagonists (VKAs) for the prevention of thromboembolism in patients with nonvalvular atrial fibrillation. However, there are few data on the efficacy and safety of NOAC therapy after cardioversion, where the risk of thromboembolic events is heightened.. We performed a random-effects meta-analysis of patients who underwent both electrical and pharmacologic cardioversion for atrial fibrillation in the RE-LY, ROCKET-AF, ARISTOTLE, ENGAGE AF-TIMI 48, and X-VeRT trials. We assessed Mantel-Haenszel pooled estimates of risk ratio (RR) and 95% confidence intervals (CIs) for stroke/systemic embolism and major bleeding at ≤42 days of follow-up.. The analysis pooled 3949 patients in whom a total of 4900 cardioversions for atrial fibrillation were performed. Compared with VKAs, NOAC therapy was associated with a similar risk of stroke/systemic embolism (RR 0.84; 95% CI, 0.34-2.04) and major bleeding (RR 1.12; 95% CI, 0.52-2.42); no significant statistical heterogeneity was found among studies (Cochrane Q P = .59, I(2) = 0% for stroke/systemic embolism; P = .47; I(2) = 0% for major bleeding).. The short-term incidences of thromboembolic and major hemorrhagic events after cardioversion on NOACs were low and comparable to those observed on dose-adjusted VKA therapy. Non-vitamin K oral anticoagulants are a reasonable alternative to VKAs in patients undergoing cardioversion.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Electric Countershock; Hemorrhage; Humans; Odds Ratio; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thromboembolism; Treatment Outcome; Warfarin

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

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

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

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

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

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

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

Historically, warfarin or aspirin have been the recommended therapeutic options for the extended treatment (>3 months) of VTE. Data from Phase III randomised controlled trials (RCTs) are now available for non-VKA oral anticoagulants (NOACs) in this indication. The current systematic review and network meta-analysis (NMA) were conducted to compare the efficacy and safety of anticoagulants for the extended treatment of VTE.. Electronic databases (accessed July 2014 and updated April 2016) were systematically searched to identify RCTs evaluating apixaban, aspirin, dabigatran, edoxaban, rivaroxaban, and warfarin for the extended treatment of VTE. Eligible studies included adults with an objectively confirmed deep vein thrombosis, pulmonary embolism or both. A fixed-effect Bayesian NMA was conducted, and results were presented as relative risks (RRs). Sensitivity analyses examining (i) the dataset employed according to the time frame for outcome assessment (ii) the model used for the NMA were conducted.. Eleven Phase III RCTs (examining apixaban, aspirin, dabigatran, rivaroxaban, warfarin and placebo) were included. The risk of the composite efficacy outcome (VTE and VTE-related death) was statistically significantly lower with the NOACs and warfarin INR 2.0-3.0 compared with aspirin, with no significant differences between the NOACs. Treatment with apixaban (RR 0.23, 95% CrI 0.10, 0.55) or dabigatran (RR 0.55, 95% Crl 0.43, 0.71) was associated with a statistically significantly reduced risk of 'major or clinically relevant non-major bleed' compared with warfarin INR 2.0-3.0. Apixaban also showed a significantly reduced risk compared with dabigatran (RR 0.42, 95% Crl 0.18, 0.97) and rivaroxaban (RR 0.23, 95% Crl 0.09, 0.59). Sensitivity analyses indicate that results were dependent on the dataset, but not on the type of NMA model employed.. Results from the NMA indicate that NOACs are an effective treatment for prevention of VTE or VTE-related death) in the extended treatment setting. However, bleeding risk differs between potential treatments, with apixaban reporting the most favourable profile compared with other NOACs, warfarin INR 2.0-3.0, and aspirin.

Topics: Administration, Oral; Anticoagulants; Clinical Trials, Phase III as Topic; Dabigatran; Humans; Long-Term Care; Network Meta-Analysis; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Treatment Outcome; Venous Thromboembolism

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

Direct oral anticoagulants (DOACs) are a relatively recent addition to the oral anticoagulant armamentarium, and provide an alternative to the use of vitamin K antagonists such as warfarin. Regardless of the type of agent used, bleeding is the major complication of anticoagulant therapy. The decision to restart oral anticoagulation following a major hemorrhage in a previously anticoagulated patient is supported largely by retrospective studies rather than randomized clinical trials (mostly with vitamin K antagonists), and remains an issue of individualized clinical assessment: the patient's risk of thromboembolism must be balanced with the risk of recurrent major bleeding. This review provides guidance for clinicians regarding if and when a patient should be re-initiated on DOAC therapy following a major hemorrhage, based on the existing evidence.

Topics: Antithrombins; Atrial Fibrillation; Dabigatran; Factor Xa Inhibitors; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Intracranial Hemorrhages; Pyrazoles; Pyridones; Recurrence; Risk Assessment; Rivaroxaban; Stroke; Thromboembolism

Direct oral anticoagulants (DOACs) have been marketed in the United States since 2010. While numerous large-scale prospective phase 3 outcomes studies have documented the effectiveness of DOACs for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, the primary safety concern with all of these drugs-as it is with the more established oral anticoagulant warfarin-is the risk of major bleeding. Postmarketing surveillance studies (PMSS) provide the opportunity to evaluate the safety of these recently approved drugs across a spectrum of patients that may be broader than those included in randomized controlled trials. This review will summarize the safety findings of numerous recently performed, large-scale PMSS evaluations, and consider the currently available evidence regarding the risks for bleeding in patients treated with DOACs, in order to give providers and patients additional evidence regarding the safety of DOACs.

Topics: Administration, Oral; Antithrombins; Atrial Fibrillation; Dabigatran; Hemorrhage; Humans; Product Surveillance, Postmarketing; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thromboembolism

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, co-administer 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; Antidotes; Antithrombins; Arginine; Blood Coagulation Factors; Clinical Protocols; Dabigatran; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Hospitals; Humans; Piperazines; Practice Guidelines as Topic; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban

Patients taking direct oral anticoagulants (DOACs) who then need an emergency invasive procedure require specialized management strategies. Appropriate patient evaluation includes assessment of the current anticoagulation state, including timing of the last dose. DOACs require particular coagulation assays to measure anticoagulation levels accurately, although standard coagulation screening tests may provide qualitative guidance. Specialty societies have endorsed general recommendations for patient management to promote hemostasis in anticoagulated patients requiring surgery or other invasive procedures. These include general stopping rules (such as ≥24 hours for low-risk procedures and ≥48 hours for high-risk surgery with normal renal function) for elective procedures. Bridging therapy when oral anticoagulant treatment is interrupted has recently been questioned, depending on the clinical scenario. Novel agents for the reversal of DOAC-induced anticoagulation have recently been developed. Idarucizumab, a humanized monoclonal antibody fragment that selectively binds dabigatran, was recently approved for clinical use in patients with life-threatening or uncontrolled bleeding, and for patients requiring emergency interventions. Idarucizumab can streamline the pre- and periprocedural anticoagulation management of dabigatran-treated patients, as it provides fast, complete, and sustainable reversibility. Andexanet alfa is an inactive, decoy factor Xa (FXa) molecule that binds FXa inhibitors, and ciraparantag is a synthetic molecule designed to bind fractionated and unfractionated heparins, and each of the currently approved DOACs. As clinical development of the additional anti-FXa-specific anticoagulant reversal agents proceeds, the respective role of each in the management of emergency bleeding events and invasive procedures will be better defined, and it is hoped they will make important contributions to patient care.

Topics: Antibodies, Monoclonal, Humanized; Anticoagulants; Antidotes; Antithrombins; Arginine; Dabigatran; Deprescriptions; Emergencies; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Piperazines; Prothrombin Time; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban; Surgical Procedures, Operative

Oral Factor Xa (FXa) inhibitors, a growing class of direct-acting anticoagulants, are frequently used to prevent stroke and systemic embolism in patients with atrial fibrillation and to prevent and treat venous thromboembolism. These drugs reduce the risk of clotting at the expense of increasing the risk of bleeding, and currently they have no specific reversal agent. However, andexanet alfa, a recombinant modified FXa decoy molecule, is in a late-phase clinical trial in bleeding patients, and ciraparantag, a small molecule that appears to reverse many anticoagulants including the FXa inhibitors, is in development. This review summarizes the published data to date on both drugs, which have the potential to change the management approach to patients with FXa inhibitor-associated major hemorrhage.

Topics: Animals; Antidotes; Arginine; Atrial Fibrillation; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Piperazines; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban; Stroke; 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

There is limited guidance available to clinicians regarding the management of antithrombotic therapy during epistaxis, whilst there has been an increase in the use of anticoagulation and antiplatelet therapy. In addition, the introduction of direct oral anticoagulants (DOACs), such as dabigatran and rivaroxaban, over the last decade has significantly increased the complexity of managing the anticoagulated epistaxis patient. We undertook a systemic literature review investigating potential management strategies for each class of anti-thrombotic therapy during epistaxis. A PubMED and Cochrane Library search was performed on 10/03/16 using, but not limited to, the search terms epistaxis, nosebleed, nose bleeding, nasal haemorrhage, nasal bleeding AND each of the following search terms: antithrombotic, anticoagulant, antiplatelet, aspirin, clopidogrel, warfarin, dabigatran, rivaroxaban, apixaban and tranexamic acid. This yielded 3815 results, of which 29 were considered relevant. Other sources such as national and international guidelines related to the management of anti-thrombotics were also utilised. We present the findings related to the management of each class of anti-thrombotic therapy during epistaxis. Overall we found a lack of evidence regarding this topic and further high quality research is needed. This is an area growing in complexity and the support of colleagues in Haematology and Cardiology is increasingly important.

Topics: Anticoagulants; Antifibrinolytic Agents; Aspirin; Clopidogrel; Dabigatran; Disease Management; Epistaxis; Humans; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Ticlopidine; Tranexamic Acid; Warfarin

Direct oral anticoagulants (DOACs) are rapidly replacing vitamin K antagonists (VKAs) for treatment of venous thromboembolism (VTE). The DOACs include dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, and edoxaban, which inhibit factor Xa. When compared with conventional VTE treatment consisting of a parenteral anticoagulant followed by a VKA, the DOACs were equally effective for prevention of recurrence, but were associated with less bleeding. With similar efficacy, better safety, and the convenience of fixed dosing without the need for routine coagulation monitoring, guidelines now recommend DOACs over VKAs for VTE treatment in patients without active cancer. Nonetheless, measures are needed to optimize the safety of DOACs. Focusing on these measures, this paper summarizes the results of phase III trials evaluating DOACs for VTE treatment; identifies which VTE patients are or are not candidates for DOACs; provides guidance on how to choose among DOACs; lists the licensed dosing information for DOACs; discusses the optimal treatment duration for VTE; describes periprocedural management of DOACs in patients requiring surgery or intervention; and finally, reviews the management of bleeding, including the role for specific reversal agents.

Topics: Administration, Oral; Anticoagulants; Blood Coagulation; Clinical Trials, Phase III as Topic; Coagulants; Dabigatran; Humans; Patient Safety; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Venous Thromboembolism

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 new direct oral anticoagulants-dabigatran etexilate, rivaroxaban, and apixaban- have predictable pharmacokinetic and pharmacodynamic profiles and are alternatives to warfarin. However, many surgeons are wary of these drugs, as there is limited evidence on how to manage bleeding in patients taking them, and only recently has a specific antidote been developed to reverse their anticoagulant effect. Management of the newer agents requires careful adherence to primary measures of bleeding care, knowledge of their mechanism of action, and familiarity with the unapproved and untested reversal strategies that may be required in patients with life-threatening bleeding.

Topics: Administration, Oral; Anticoagulants; Antidotes; Antithrombins; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Hemostasis, Surgical; Humans; Oral Surgical Procedures; Pyrazoles; Pyridones; Rivaroxaban; 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

Direct oral anticoagulants (DOACs) have been marketed in the United States since 2010. While numerous large-scale prospective phase 3 outcomes studies have documented the effectiveness of DOACs for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, the primary safety concern with all of these drugs-as it is with the more established oral anticoagulant warfarin-is the risk of major bleeding. Postmarketing surveillance studies (PMSS) provide the opportunity to evaluate the safety of these recently approved drugs across a spectrum of patients that may be broader than those included in randomized controlled trials. This review will summarize the safety findings of numerous recently performed, large-scale PMSS evaluations, and consider the currently available evidence regarding the risks for bleeding in patients treated with DOACs, in order to give providers and patients additional evidence regarding the safety of DOACs.

Topics: Anticoagulants; Dabigatran; Hemorrhage; Humans; Product Surveillance, Postmarketing; Pyrazoles; Pyridones; Rivaroxaban

Among patients with atrial fibrillation, prophylaxis for stroke prevention with the use of anticoagulation is well established in the general population. A number of randomized controlled trials and evidence-based risk prediction tools clearly delineate the benefit and risks of therapy. Despite the high incidence of atrial fibrillation in the late stage CKD and ESRD populations, little high quality evidence exists in these populations. Is it appropriate then to extrapolate findings from the general population to those with CKD/ESRD? In our view, too much uncertainty exists regarding proof of efficacy with clear signals of harm. Routine anticoagulation for stroke prevention in atrial fibrillation is not recommended for the majority of CKD and ESRD patients.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Hemorrhage; Humans; Kidney Failure, Chronic; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Stroke; Warfarin

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

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

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

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

Venous thromboembolism (VTE) causes substantial morbidity and mortality worldwide. The traditional treatment of VTE, with an initial therapy with (low molecular weight) heparin or fondaparinux and a continued treatment with vitamin K antagonists, is effective but has limitations.. The current review summarizes the results of the Phase III trials with the new oral direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban and provides a meta-analysis of these trials in the subgroups of elderly patients (> 75 years) and patients with impaired renal function.. The practical use of direct Xa inhibitors in the treatment of VTE in general and in specific subgroups is discussed. For elderly patients, patients with extremes of body weight, cancer patients or patients with moderate renal impairment, pooled data suggest that the direct oral Xa inhibitors are a reasonable alternative to standard therapy. For other indications, such as treatment of VTE in children, during pregnancy or in the context of heparin-induced thrombocytopenia, further data from clinical trials are needed.

Topics: Administration, Oral; Clinical Trials, Phase III as Topic; Factor Xa; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Venous Thromboembolism

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

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

Since the introduction of NOAC (non-vitamin K antagonist oral anticoagulants) in 2011 as thromboprophylactic treatment for patients with atrial fibrillation, AF, the number of patients with a diagnosis of atrial fibrillation has increased markedly in our health care registers. The proportion of patients treated with warfarin or NOAC has increased from 47 % to 58 % in 2013. The use of acetylsalicylic acid in patients is decreasing rapidly in patients with AF. NOAC are mostly prescribed by specialists and are mainly used in younger patients with lower CHA2DS2-VASc scores and lower risk for renal insufficiency and bleeding.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Aspirin; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cohort Studies; Dabigatran; Drug Prescriptions; Drug Utilization; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Morpholines; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Thiophenes; Warfarin

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

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

The new oral anticoagulants (NOAC) dabigatran etexilate, rivaroxaban, and apixaban show similar efficacy for stroke prevention in patients with atrial fibrillation (AF) as the vitamin K antagonist warfarin. Absorption of NOACs is dependent on the intestinal P-glycoprotein (P-gp) system and P-gp activity is modulated by a variety of drugs and food components.. The aim of this review is to give an overview of P-gp-associated drug-drug and drug-food interactions with NOACs in AF patients.. A literature search was carried out by screening MEDLINE for the terms dabigatran, rivaroxaban, apixaban, P-glycoprotein, and atrial fibrillation from 1998 to 2013. Randomized clinical trials, longitudinal studies, case series, and case reports were included.. Concomitant medication with proton pump inhibitors, amiodarone, clarithromycin, and verapamil increased bioavailability whereas rifampicin decreased the bioavailability of dabigatran. Coadministration of erythromycin, clarithromycin, fluconazole, ketoconazole, and ritonavir increased rivaroxaban plasma concentrations. No data were found on apixaban and P-gp-modulating drugs or on NOACs and food components modulating P-gp. The clinical relevance of interactions between NOACs and P-gp-modulating drugs or food components is largely unknown as bleeding complications under NOACs and P-gp-inhibiting drugs are mainly reported from patients with concomitant renal failure.. There is an urgent need to investigate the role of P-gp-modulating substances as potential sources of drug-drug and drug-food interactions. A thorough analysis of the data accumulated in the three large NOAC trials regarding the role of P-gp-modulating drugs in bleeding and embolic events is desirable. Pharmacological studies should investigate the influence of P-gp-modulating drugs and food on NOAC plasma concentrations and coagulation parameters. When prescribing NOACs, patients should be informed about the potential interactions with drugs and herbal drugs. Patients who develop bleeding or embolic events under treatment with NOACs should be investigated for co-medications as well as for over-the-counter drugs and dietary habits. In post-marketing surveillance of NOACs, the association with drug or food intake with complications, bleeding, and embolic events should be registered.

Topics: Administration, Oral; Antithrombins; ATP Binding Cassette Transporter, Subfamily B, Member 1; Atrial Fibrillation; Dabigatran; Drug Interactions; Factor Xa Inhibitors; Humans; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Treatment Outcome

The development of new orally administered anticoagulants, such as dabigatran, rivaroxaban, and apixaban, in the past few years has focused on avoiding some of the drawbacks associated with warfarin. This work aims to illustrate the main features of the most commonly used new oral anticoagulants, reviewing the current literature on the management of patients taking these drugs and needing oral and implant surgery, and discussing the currently proposed related guidelines.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Dabigatran; Dental Care for Chronically Ill; Factor Xa Inhibitors; Humans; Oral Hemorrhage; Oral Surgical Procedures; Pyrazoles; Pyridones; Rivaroxaban; Warfarin

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

We summarize the available data related to reversing the anticoagulant effect of the oral direct thrombin and factor Xa inhibitors and provide our opinion on treating patients presenting with severe and life-threatening hemorrhage related to these agents.. No specific antidotes are currently available for the oral direct thrombin and factor Xa inhibitors but two promising agents are under investigation in phase 3 trials. No data are available on reversing these agents in bleeding patients. Activated charcoal may be effective in reducing factor Xa inhibitor absorption up to 6 h after ingestion. Animal models suggest that unactivated 4-factor prothrombin complex concentrate may be an effective reversal agent. Recent data in warfarin-treated patients suggest that 4-factor prothrombin complex concentrate may provide more rapid and effective hemostasis than fresh frozen plasma.. In the absence of evidence in bleeding patients, animal models and ex-vivo studies suggest administration of coagulant factors in the form of hemostatic agents may be of benefit in reversing the effect of direct thrombin and factor Xa inhibitors. Specific reversal agents and clinical data in patients with hemorrhage remain an unmet need.

Topics: Animals; Antidotes; Antithrombins; Benzimidazoles; beta-Alanine; Coagulants; Dabigatran; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Humans; Models, Animal; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; 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

Novel oral anticoagulants are emerging options for the prevention and treatment of thromboembolic diseases. They are increasingly used in clinical practice due to their simplicity of use and clinical benefits, but an important step is to evaluate their cost-effectiveness. The aim of the AFFORD study (A Review of Cost EFFectiveness of Novel ORal Anticoagulant Drugs) was to perform a systematic review of cost-effectiveness studies of novel oral anticoagulants for stroke prevention in non-valvular atrial fibrillation (AF).. A systematic review of the literature was conducted by searching the PubMed, Embase, Scopus, Cochrane and Web of Knowledge databases to identify all cost-effectiveness studies of novel oral anticoagulants for stroke prevention in AF.. The search identified 27 studies, 18 with dabigatran, three with apixaban, two with rivaroxaban and four with at least two of these drugs. The incremental cost-effectiveness ratios were 30 405 ± 16 101 euros per quality-adjusted life-year (QALY) for dabigatran 110 mg, 17 566 ± 16 902 euros/QALY for dabigatran 150 mg, 8102 ± 3252 euros/QALY for age-adjusted dabigatran, 11 897 ± 3341 euros/QALY for apixaban and 17 960 ± 12 005 euros/QALY for rivaroxaban.. The present systematic review demonstrates that novel oral anticoagulants are cost-effective for stroke prevention in AF.

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

A meta-analysis of randomized controlled trials (RCTs) was performed to compare the efficacy and safety of direct factor Xa inhibitors (rivaroxaban and apixaban) with enoxaparin for the prevention of venous thromboembolism (VTE) after total knee replacement.. A systematic literature search in Medline, EMBASE, EBSCO, Springer, Ovid and Cochrane library databases was performed to identify RCTs comparing rivaroxaban/apixaban with enoxaparin for the prevention of VTE after total knee replacement. The outcomes including deep vein thrombosis (DVT), pulmonary embolism (PE) and major bleeding were pooled using risk ratios (RRs) with their 95% confidence intervals (95% CIs) as statistic.. A total of 6 RCTs with 13,790 patients were included in this meta-analysis. Overall, the incidence of DVT was significantly decreased with the use of direct Xa inhibitors (both twice daily [b.i.d] and once daily [q.d.] regimes) comparing with the enoxaparin treatment (P<0.01); however, there was no significant influencing difference between direct Xa inhibitors (b.i.d. regime) and enoxaparin on the incidence of PE (P=0.06), while significantly lower rate was found for q.d. regime of direct Xa inhibitors (P=0.02). With respect to major bleeding, the pooled analysis did not demonstrate a significant difference between direct Xa inhibitors (b.i.d. and q.d. regimes) and enoxaparin (30mg and 40mg b.i.d.).. In conclusion, our results confirmed that direct Xa inhibitors (rivaroxaban and apixaban) were more effective for prevention of VTE after total knee replacement as compared with enoxaparin, without increasing major bleeding risk.

Topics: Anticoagulants; Arthroplasty, Replacement, Knee; Enoxaparin; Factor Xa Inhibitors; Hemorrhage; Humans; Pulmonary Embolism; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Treatment Outcome; Venous Thromboembolism; Venous Thrombosis

New oral anticoagulants represent an alternative to standard therapy with vitamin K antagonists but data regarding gastrointestinal bleeding are still unclear.. To investigate if new oral anticoagulants are associated with an enhanced risk of gastrointestinal bleeding vs warfarin in patients with atrial fibrillation.. Meta-analysis of phase three randomized controlled trials to compare the incidence of gastrointestinal bleeding in atrial fibrillation patients treated with new oral anticoagulants (apixaban, dabigatran, edoxaban and rivaroxaban) vs warfarin.. Four studies including 71,302 patients were selected. Compared with warfarin, new oral anticoagulants significantly increased gastrointestinal bleeding (RR: 1.23; 95% CI 1.03-1.46; p=0.01). Rivaroxaban (RR: 1.46; 95% CI 1.2-1.8; p<0.001) and high dosages of edoxaban (RR: 1.22; 95% CI 1.01-1.47; p=0.038) and dabigatran (RR: 1.50; 95% CI 1.20-1.88; p<0.001) significantly increased gastrointestinal bleeding while a null effect was detected with apixaban.. This meta-analysis suggests that rivaroxaban and high dosages of dabigatran and edoxaban should be avoided in patients at high risk of gastrointestinal bleeding.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Gastrointestinal Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Risk Factors; Rivaroxaban; Thiazoles; Warfarin

Anticoagulant medications help to reduce the risk of thromboembolic events after total hip arthroplasty and total knee arthroplasty. Traditionally, this has been accomplished with medications, such as low-molecular-weight heparin and warfarin. However, these traditional anticoagulants possess a variety of shortcomings that leave much room for improvement. A new class of oral anticoagulants is now available, and present a more convenient option for safe and efficacious thromboprophylaxis in post arthroplasty patients, particularly in the outpatient setting. This review focuses on the direct thrombin inhibitor, dabigatran, and the selective factor Xa inhibitors, rivaroxaban and apixaban, and the clinical data to date about their use in total hip arthroplasty and total knee arthroplasty patients.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Benzimidazoles; beta-Alanine; Dabigatran; Drug Administration Schedule; Elective Surgical Procedures; Factor Xa Inhibitors; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Thiophenes; Thromboembolism; Treatment Outcome

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

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

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cerebral Hemorrhage; Contraindications; Dabigatran; Drug Administration Schedule; Drug Interactions; Endovascular Procedures; Factor Xa Inhibitors; Female; Humans; Infusions, Intravenous; Kidney Function Tests; Male; Middle Aged; Practice Guidelines as Topic; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Thrombectomy; Thrombolytic Therapy; Tissue Plasminogen Activator

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

Four new oral anticoagulants (NOAC), apixaban, rivaroxaban, edoxaban, and dabigatran, are now available in the USA; however, only apixaban and rivaroxaban are FDA approved for the prevention of venous thromboembolism following orthopedic surgery. Apixaban, rivaroxaban, and edoxaban's anticoagulant activity can be measured using a chromogenic anti-factor Xa assay but there is no widely available means of measuring dabigatran blood levels. None of the NOAC has an antidote. Dabigatran is 80% renally excreted, and patients with atrial fibrillation taking dabigatran for stroke prevention should stop the drug 4-5 days prior to major orthopedic surgery. Apixaban, rivaroxaban, and edoxaban should be held for 48 h preoperatively in this setting.

Topics: Administration, Oral; Anticoagulants; Dabigatran; Humans; Orthopedic Procedures; Postoperative Care; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Venous Thromboembolism

Warfarin, the most commonly used of the vitamin K antagonists, has been a mainstay of oral anticoagulation for decades. However, its usage is limited by morbidity and mortality secondary to bleeding as well as a cumbersome therapeutic monitoring process. In the past several years, a number of competing novel oral anticoagulants (NOACs) have been developed, each of which aspires to match or exceed warfarin's effectiveness while mitigating bleeding risk and eliminating therapeutic monitoring requirements. At present, 1 oral direct thrombin inhibitor and 2 direct factor Xa inhibitors are approved by the US Food and Drug Administration. Here, we compare the clinical efficacy and safety profiles of these new drugs. In addition, we discuss various laboratory assays that may be useful to measure these drugs in certain clinical circumstances. Finally, we discuss emerging strategies to reverse these agents in an emergency. The purpose of this article is to provide a framework for practicing pathologists to advise clinicians on NOAC laboratory measurement and management of NOAC-associated bleeding.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Benzimidazoles; beta-Alanine; Blood Coagulation; Dabigatran; Drug Monitoring; Factor Xa Inhibitors; Hemorrhage; Humans; Laboratories; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thromboembolism; Treatment Outcome; Warfarin

Modern direct-acting anticoagulants are rapidly replacing vitamin K antagonists (VKA) in the management of millions of patients worldwide who require anticoagulation. These drugs include agents that inhibit activated factor X (FXa) (such as apixaban and rivaroxaban) or thrombin (such as dabigatran), and are collectively known today as non-VKA oral anticoagulants (NOACs). Since bleeding is the most common and most dangerous side effect of long-term anticoagulation, and because NOACs have very different mechanisms of action and pharmacokinetics compared with VKA, physicians are naturally concerned about the lack of experience regarding frequency, management and outcome of NOAC-associated bleeding in daily care. This review appraises trial and registry (or "real-world") data pertaining to bleeding complications in patients taking NOACs and VKA and provides practical recommendations for the management of acute bleeding situations.

Topics: Antithrombins; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Outcome Assessment, Health Care; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Thromboembolism; Vitamin K

The incidence of post-operative arterial thrombosis (AT) (acute myocardial infarction [AMI] and ischaemic stroke) is increased in patients undergoing total hip replacement (THR) or total knee replacement (TKR). We compared the incidence of post-operative AT in non-vitamin K antagonist oral anticoagulants (NOACs)-treated and enoxaparin-treated patients, performing a systematic review of phase III randomised controlled trials (RCTs) of venous thromboembolism (VTE) prophylaxis in THR and TKR. Studies were identified by electronic search of MEDLINE and EMBASE database until July 2014. Differences between NOACs and enoxaparin groups in the efficacy and safety outcomes were expressed as odds ratios (ORs) with pertinent 95 % confidence intervals (95 % CI). Statistical heterogeneity was assessed with the I² statistic. Eleven phase III RCTs for a total of 31,319 patients were included. Patients underwent TKR in six studies and THR in five studies. The NOACs under study were dabigatran (four studies), apixaban (three studies) and rivaroxaban (four studies). AT occurred in 0.23 % of patients on NOACs and in 0.27 % of patients on enoxaparin: the OR at fixed-effect model was 0.86 (95 % CI 0.53-1.40; I² 11 %). No differences in AT incidence among the three NOACs were observed. The incidence of major and clinically relevant bleeding was similar in NOACs and enoxaparin groups (OR 1.03, 95 % CI 0.92-1.15; I² 38 %). In conclusion, in RCTs of pharmacological VTE prophylaxis in patients undergoing THR or TKR, there was no difference in the incidence of post-operative AT among patients treated with NOACs, compared to those treated with enoxaparin.

Topics: Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Brain Ischemia; Clinical Trials, Phase III as Topic; Dabigatran; Enoxaparin; Factor Xa Inhibitors; Female; Humans; Incidence; Male; Middle Aged; Multicenter Studies as Topic; Myocardial Infarction; Postoperative Complications; Postoperative Hemorrhage; Prothrombin; Pulmonary Embolism; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Treatment Outcome

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

Recently, novel oral anticoagulants (NOACs) have been approved for stroke prevention in patients with atrial fibrillation (AF). Although these agents overcome some disadvantages of warfarin, they are associated with increased costs. In this review, we will provide an overview of the cost-effectiveness of NOACs for stroke prevention in AF. Our comments and conclusions are limited to studies directly comparing all available NOACs within the same framework. The available cost-effectiveness analyses suggest that NOACs are cost-effective compared to warfarin, with apixaban likely being most favorable. However, significant limitations in these models are present and should be appreciated when interpreting their results.

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

Non-VKA oral anticoagulants (NOACs) have now widely reached the lucrative market of anticoagulation. While the marketing authorization holders claimed that no routine monitoring is required and that these compounds can be given at fixed doses, several evidences arisen from the literature tend to demonstrate the opposite. New data suggests that an assessment of the response at the individual level could improve the benefit-risk ratio of at least dabigatran. Information regarding the association of rivaroxaban and apixaban exposure and the bleeding risk is available in the drug approval package on the FDA website. These reviews suggest that accumulation of these compounds increases the risk of experiencing a bleeding complication. Therefore, in certain patient populations such as patients with acute or chronic renal impairment or with multiple drug interactions, measurement of drug exposure may be useful to ensure an optimal treatment response. More specific circumstances such as patients experiencing a haemorrhagic or thromboembolic event during the treatment duration, patients who require urgent surgery or an invasive procedure, or patient with a suspected overdose could benefit from such a measurement. This paper aims at providing guidance on how to best estimate the intensity of anticoagulation using laboratory assays in daily practice.

Topics: Anticoagulants; Blood Coagulation; Dabigatran; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Thiophenes; Thromboembolism

To review current literature for target-specific oral anticoagulants (TSOACs) and provide critical analysis for dosing recommendations in special population groups.. A literature search was conducted in Medline (1996 to April week 2 2015) and Embase (1980 to 2015 week 16) using key terms dabigatran, rivaroxaban, apixaban, edoxaban, kidney diseases, liver diseases, elderly, obesity, and special populations.. Randomized controlled trials in English assessing efficacy and safety of TSOACs in healthy adults and special populations were selected for analysis.. Phase 3 trials for TSOACs predominately excluded patients with severe renal impairment or active liver disease. There were no exclusion criteria based on age, body weight or body mass index. Additional conclusions were made in special populations, including those with renal or liver impairment and obese and elderly patients, based on secondary analyses, pharmacokinetic, and pharmacodynamic studies.. Pharmacokinetic and pharmacodynamic changes associated special populations may alter clinical decision with regard to drug selection and dosing. It is valuable to understand the rationale for labeled dosing recommendations in nonvalvular atrial fibrillation and venous thromboembolism treatment and prevention, particularly in patients that fall into special population groups. Furthermore, the use of TSOACs is likely to increase as clinicians gain experience with these agents and additional TSOACs and indications are approved.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Clinical Trials as Topic; Dabigatran; Humans; Kidney Diseases; Liver Diseases; Obesity; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiazoles; Venous Thromboembolism

Deep vein thrombosis (DVT) is a condition in which a clot forms in the deep veins, most commonly of the leg. It occurs in approximately 1 in 1,000 people. If left untreated, the clot can travel up to the lungs and cause a potentially life-threatening pulmonary embolism (PE). Previously, a DVT was treated with the anticoagulants heparin and vitamin K antagonists. However, two forms of novel oral anticoagulants (NOACs) have been developed: oral direct thrombin inhibitors (DTI) and oral factor Xa inhibitors. The new drugs have characteristics that may be favourable over conventional treatment, including oral administration, a predictable effect, lack of frequent monitoring or re-dosing and few known drug interactions. To date, no Cochrane review has measured the effectiveness and safety of these drugs in the treatment of DVT.. To assess the effectiveness of oral DTIs and oral factor Xa inhibitors for the treatment of DVT.. The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched January 2015) and the Cochrane Register of Studies (last searched January 2015). We searched clinical trials databases for details of ongoing or unpublished studies and the reference lists of relevant articles retrieved by electronic searches for additional citations.. We included randomised controlled trials in which people with a DVT confirmed by standard imaging techniques, were allocated to receive an oral DTI or an oral factor Xa inhibitor for the treatment of DVT.. Two review authors (LR, JM) independently extracted the data and assessed the risk of bias in the trials. Any disagreements were resolved by discussion with the third review author (PK). We performed meta-analyses when we considered heterogeneity low. The two primary outcomes were recurrent VTE and PE. Other outcomes included all-cause mortality and major bleeding. We calculated all outcomes using an odds ratio (OR) with a 95% confidence interval (CI).. We included 11 randomised controlled trials of 27,945 participants. Three studies tested oral DTIs (two dabigatran and one ximelagatran), while eight tested oral factor Xa inhibitors (four rivaroxaban, two apixaban and two edoxaban). We deemed all included studies to be of high methodological quality and low risk of bias. The quality of the evidence was graded as high as the outcomes were direct and effect estimates were consistent and precise, as reflected in the narrow CIs around the ORs. Meta-analysis of three studies (7596 participants) comparing oral DTIs with standard anticoagulation groups showed no difference in the rate of recurrent VTE (OR 1.09; 95% CI 0.80 to 1.49), recurrent DVT (OR 1.08; 95% CI 0.74 to 1.58), fatal PE (OR 1.00; 95% CI 0.27 to 3.70), non-fatal PE (OR 1.12; 95% CI 0.66 to 1.90) or all-cause mortality (OR 0.82; 95% CI 0.60 to 1.13). However, oral DTIs were associated with reduced bleeding (OR 0.68; 95% CI 0.47 to 0.98). Meta-analysis of eight studies (16,356 participants) comparing oral factor Xa inhibitors with standard anticoagulation demonstrated a similar rate of recurrent VTE between the two treatments (OR 0.89; 95% CI 0.73 to 1.07). Oral factor Xa inhibitors were associated with a lower rate of recurrent DVT (OR 0.75; 95% CI 0.57 to 0.98). However, this was a weak association, heavily dependent on one study. The rate of fatal (OR 1.20; 95% CI 0.71 to 2.03), non-fatal PE (OR 0.94; 95% CI 0.68 to 1.28) and all-cause mortality (OR 0.90; 95% CI 0.65 to 1.23) was similar between the two treatment groups. Oral factor Xa inhibitors were also associated with reduced bleeding (OR 0.57; 95% CI 0.43 to 0.76). None of the included studies measured post-thrombotic syndrome or health-related quality of life.. NOACs such as DTIs and factor Xa inhibitors may be an effective and safe alternative to conventional anticoagulation treatment for acute DVT.

Topics: Administration, Oral; Antithrombins; Azetidines; Benzylamines; Dabigatran; Factor Xa Inhibitors; Humans; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiazoles; Venous Thrombosis

Case reports and analyses of clinical studies and of pharmacovigilance data suggest that new oral anticoagulants (NOACs) are associated with a small risk for hepatotoxicity. The objective of this publication is to summarize the current data about this subject, with a special emphasis on pharmacovigilance data in the World Health Organization (WHO) Global Individual Case Safety Reports (ICSR) database and on potential mechanisms of hepatotoxicity. For that, all available case reports as well as published analyses of clinical studies were obtained with a detailed search in PubMed. In addition, pharmacovigilance data from VigiBase(®), the WHO Global ICRS database, were extracted and analyzed. The data show that liver injury associated with NOACs was reported in clinical studies and in pharmacovigilance databases. Several case reports described potentially life-threatening hepatotoxicity in patients treated with rivaroxaban or dabigatran. For rivaroxaban, most affected patients were symptomatic and liver injury was most often hepatocellular or mixed. The frequency was between 0.1 and 1 % in clinical studies and was by trend lower than for comparators (mostly enoxaparin or warfarin). Comparing the pharmacovigilance reports for the individual NOACs, more hepatic adverse events were reported for rivaroxaban than for dabigatran or apixaban. With the exception of edoxaban, for which only few reports are available, patients with acute liver failure have been reported for every NOAC, but most patients had concomitant drugs or diseases. So far, there are no clear mechanisms explaining the hepatotoxicity of these drugs. We conclude that hepatotoxicity appears to be associated with all NOACs currently on the market. Hepatotoxicity associated with NOACs is idiosyncratic; it appears at therapeutic doses, is rare and the mechanism is not related to the pharmacological action of these drugs. Prescribers should inform patients about possible symptoms of hepatotoxicity and stop these drugs in patients presenting with severe liver injury.

Topics: Administration, Oral; Animals; Anticoagulants; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles

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

Topics: Administration, Oral; Aged; Anticoagulants; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Contraindications; Dabigatran; Drug Interactions; Humans; International Normalized Ratio; Male; Morpholines; Pulmonary Embolism; Pyrazoles; Pyridones; Recurrence; Rivaroxaban; Thiophenes; Venous Thromboembolism

The risk of venous thromboembolism (VTE) increases with age. New oral anticoagulants (NOACs) have been increasingly studied for VTE prophylaxis in patients with elective postarthroplasty. Although the elderly population accounts for a significant proportion of patients requiring VTE prophylaxis, safety and efficacy of NOACs in this subgroup for VTE prophylaxis has not been well studied. Relevant studies were identified through electronic literature searches of MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov (from inception to 12 August 2014). Phase III randomized controlled trials that compared NOACs against low-molecular-weight heparin (LMWH) in the prevention of VTE prophylaxis in patients with elective postarthroplasty were included. We defined our elderly population as adults of at least 75 years and assessed the reported safety and efficacy outcomes with NOACs in this population. Study-specific odds ratios (ORs) were calculated and between-study heterogeneity was assessed using the I statistic. In nine trials involving 29 403 patients, the risk of VTE or VTE-related deaths in elderly patients with elective postarthroplasty was similar with NOACs compared with LMWH (OR 0.62, 95% confidence interval 0.30-1.26; P = 0.18; I = 44%) but bleeding risk was significantly lower (OR 0.71, 95% confidence interval 0.53-0.94; P = 0.02; I = 0%). Analysis of individual NOACs showed superior efficacy but similar safety for apixaban when compared with LMWH. Efficacy and safety profiles of rivaroxaban and dabigatran were similar to LMWH. In elderly patients with elective postarthroplasty, NOACs have similar efficacy but superior safety when compared with enoxaparin for VTE prophylaxis.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Dabigatran; Female; Heparin, Low-Molecular-Weight; Humans; Male; Odds Ratio; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Survival Analysis; Treatment Outcome; Venous Thromboembolism

Thrombo-embolic prophylaxis is a key element within the therapy of atrial fibrillation/atrial flutter. Besides new oral anticoagulants the concept of left atrial appendage occlusion has approved to be a good alternative option, especially in patients with increased risk of bleeding.

Topics: Anticoagulants; Atrial Appendage; Atrial Fibrillation; Atrial Flutter; Benzimidazoles; beta-Alanine; Combined Modality Therapy; Contraindications; Dabigatran; Hemorrhage; Morpholines; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Thiophenes; Thromboembolism; Vitamin K

Non-vitamin K antagonist oral anticoagulants (NOACs), are direct anticoagulants which inhibit specific coagulation factors and function as anticoagulants. Three NOACs are currently licensed in the United Kingdom: dabigatran, a thrombin inhibitor, and rivaroxaban and apixaban, antagonists of factor Xa. They are set to change the anticoagulant landscape, which was previously ruled by warfarin and heparins. Their advantages including oral formulations, rapid onset and offset of action, predictable pharmacokinetics, no requirement for routine blood monitoring or dose adjustment and very few drug interactions. The increasing use of these drugs means the acute medicine physicians are likely to encounter patients who have been taking them. This article reviews some of the challenging clinical situations in which this may arise.

Topics: Anticoagulants; Dabigatran; Emergency Medicine; Humans; Pyrazoles; Pyridones; Rivaroxaban; Stroke; United Kingdom

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

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

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

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

The treatment of pulmonary embolism is going to be deeply modified by the development of Direct Oral Anticoagulants (DOACs). There are currently three anti-Xa factors (rivaroxaban, apixaban, edoxaban) and one anti-IIa factor (dabigatran) labeled by the FDA and the EMA. All these drugs are direct anticoagulant, orally effective, without the need for adaptation to hemostasis test. As kidney excretion is involved for all of them, they are contra-indicated in patients with severe renal failure (creatinine clearance < 30 mL/min according to Cockcroft & Gault formula). All the anti-Xa factor drugs are metabolized by liver cytochromes and then contra-indicated in case of liver insufficiency. Of note, the four DOACS have been evaluated in non-inferiority trials, including one open-label trial (the EINSTEIN program with the rivaroxaban). Moreover, two of them (rivaroxaban and apixaban) were evaluated in a single drug approach (provided initial increased doses: 15 mg bid during 21 days for rivaroxaban and 10 mg bid during 7 days for apixaban) whereas the two others (edoxaban and dabigatran) were evaluated after at least 5 days of parenteral heparin. They were found to be non-inferior to the conventional treatment, but also seem to be associated with a decreased risk of major bleeding, in a quite young and without significant comorbidities population. The risk/benefit ratio of DOACs in specific subgroups deserves prospective validations.

Topics: Antithrombins; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Humans; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Rivaroxaban; Thiazoles; Venous Thromboembolism

Pulmonary embolism is a potentially life-threatening condition in which a clot can travel from the deep veins, most commonly in the leg, up to the lungs. Previously, a pulmonary embolism was treated with the anticoagulants heparin and vitamin K antagonists. Recently, however, two forms of direct oral anticoagulants (DOACs) have been developed: oral direct thrombin inhibitors (DTI) and oral factor Xa inhibitors. The new drugs have characteristics that may be favourable over conventional treatment, including oral administration, a predictable effect, lack of frequent monitoring or re-dosing and few known drug interactions. To date, no Cochrane review has measured the effectiveness and safety of these drugs in the long-term treatment (minimum duration of three months) of pulmonary embolism.. To assess the effectiveness of oral DTIs and oral factor Xa inhibitors for the long-term treatment of pulmonary embolism.. The Cochrane Vascular Trials Search Co-ordinator searched the Specialised Register (last searched January 2015) and the Cochrane Register of Studies (last searched January 2015). Clinical trials databases were also searched for details of ongoing or unpublished studies. We searched the reference lists of relevant articles retrieved by electronic searches for additional citations.. We included randomised controlled trials in which patients with a pulmonary embolism confirmed by standard imaging techniques were allocated to receive an oral DTI or an oral factor Xa inhibitor for the long-term (minimum duration three months) treatment of pulmonary embolism.. Two review authors (LR, JM) independently extracted the data and assessed the risk of bias in the trials. Any disagreements were resolved by discussion with the third author (PK). We used meta-analyses when we considered heterogeneity low. The two primary outcomes were recurrent venous thromboembolism and pulmonary embolism. Other outcomes included all-cause mortality and major bleeding. We calculated all outcomes using an odds ratio (OR) with a 95% confidence interval (CI).. We included five randomised controlled trials with a total of 7897 participants. Two studies tested oral DTIs (dabigatran) and three studies tested oral factor Xa inhibitors (one rivaroxaban, one edoxaban and one apixaban).Analysis showed no difference in the effectiveness of oral DTIs and standard anticoagulation in preventing recurrent pulmonary embolism (OR 1.02, 95% CI 0.50 to 2.04; two studies; 1602 participants; high quality evidence), recurrent venous thromboembolism (OR 0.93, 95% CI 0.52 to 1.66; two studies; 1602 participants; high quality evidence), deep vein thrombosis (DVT) (OR 0.79, 95% CI 0.29 to 2.13; two studies; 1602 participants; high quality evidence) and major bleeding (OR 0.50, 95% CI 0.15 to 1.68; two studies; 1527 participants; high quality evidence).For oral factor Xa inhibitors, when we combined the three included studies together in meta-analyses, there was significant heterogeneity for recurrent pulmonary embolism (OR 1.08, 95% CI 0.46 to 2.56; two studies; 4509 participants; I(2) = 58%; moderate quality evidence). The oral factor Xa inhibitors were no more or less effective in the prevention of recurrent venous thromboembolism (OR 0.85, 95% CI 0.63 to 1.15; three studies; 6295 participants; high quality evidence), DVT (OR 0.72, 95% CI 0.39 to 1.32; two studies; 4509 participants; high quality evidence), all-cause mortality (OR 1.16, 95% CI 0.79 to 1.70; one study; 4817 participants; moderate quality evidence) or major bleeding (OR 0.97, 95% CI 0.59 to 1.62; two studies; 4507 participants; high quality evidence). None of the studies measured quality of life.. Moderate to high quality evidence suggests that there are no differences between DOACs and standard anticoagulation for the long-term treatment of pulmonary embolism, for the outcomes recurrent pulmonary embolism, recurrent venous thromboembolism, DVT, all-cause mortality and major bleeding.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Dabigatran; Factor Xa Inhibitors; Humans; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Recurrence; Rivaroxaban; Secondary Prevention; Thiazoles; Venous Thromboembolism; Venous Thrombosis

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

This study aimed to ascertain otolaryngologists' current knowledge of new (e.g. apixaban, rivaroxaban) and old (e.g. warfarin) anticoagulant medications, and to provide an educational overview of new anticoagulants for use by surgeons.. A questionnaire survey was distributed across the Wessex region, UK, to ascertain the levels of knowledge of and confidence in managing patients taking various anticoagulants. In total, 50 questionnaires were completed (41 by trainees and 9 by consultants). A literature review of new anticoagulant medications was then conducted.. In general, there was poor clinical and pharmacokinetic knowledge of newly licensed anticoagulant medications. Respondents were more confident in the use of older vs newer forms of anticoagulants. This was true across all grades of doctors, but particularly at the senior level. All respondents stated that they would like to see an educational resource on anticoagulants.. Knowledge of newly licensed anticoagulation medications is poor. This study has produced an educational resource for the management of anticoagulant agents. A thorough knowledge of these drugs is essential for the acute management of bleeding patients and in peri-operative surgical planning.

Topics: Administration, Oral; Adult; Anticoagulants; Clinical Competence; Cross-Sectional Studies; Dabigatran; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hemorrhage; Humans; Male; Middle Aged; Otolaryngology; Practice Guidelines as Topic; Practice Patterns, Physicians'; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Surveys and Questionnaires; United Kingdom

Stroke prevention in patients with nonvalvular atrial fibrillation relies on an assessment of the individual risks for stroke and bleeding. Patients at high risk for stroke are candidates for anticoagulant therapy. Anticoagulants, however, have substantial bleeding risks that must be weighed in the therapeutic decision. Warfarin has been the traditional choice, but the recently introduced novel oral anticoagulants offer similar efficacy with less bleeding risk. Additionally, they do not require monitoring and have fewer drug interactions and dietary restrictions than warfarin. Several devices, which isolate the left atrial appendage, have become available as treatment options for patients with elevated risks of both thromboembolism and bleeding complications.

Topics: Anticoagulants; Aspirin; Atrial Appendage; Atrial Fibrillation; Dabigatran; Equipment and Supplies; Hemorrhage; Humans; Ligation; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thromboembolism; Warfarin

Anticoagulation with low molecular weight heparin and vitamin K antagonists is the current standard of care (SOC) for venous thromboembolism (VTE) treatment and prevention. Although novel oral anti-coagulants (NOACs) have been compared with SOC in this indication, no head-to-head randomised controlled trials (RCTs) have directly compared NOACs. A systematic review and network meta-analysis (NMA) were conducted to compare the efficacy and safety of NOACs for the initial and long-term treatment of VTE.. Electronic databases (accessed July 2014) were systematically searched to identify RCTs evaluating apixaban, dabigatran, edoxaban, and rivaroxaban versus SOC. Eligible patients included adults with an objectively confirmed deep vein thrombosis (DVT), pulmonary embolism (PE) or both. A fixed-effect Bayesian NMA was conducted for outcomes of interest, and results were presented as relative risks (RR) and 95% credible intervals (Crl).. Six Phase III RCTs met criteria for inclusion: apixaban (one RCT; n = 5,395); rivaroxaban (two RCTs; n = 3,423/4,832); dabigatran (two RCTs; n = 2,539/2,568); edoxaban (one RCT; n = 8,240). There were no statistically significant differences between the NOACs with regard to the risk of 'VTE and VTE-related death. Apixaban treatment was associated with the most favourable safety profile of the NOACs, showing a statistically significantly reduced risk of 'major or clinically relevant non-major (CRNM) bleed' compared with rivaroxaban (0.47 [0.36, 0.61]), dabigatran (0.69 [0.51, 0.94]), and edoxaban (0.54 [0.41, 0.69]). Dabigatran was also associated with a significantly lower risk of 'major or CRNM bleed' compared with rivaroxaban (0.68 [0.53, 0.87]) and edoxaban (0.77 [0.60, 0.99]).. Indirect comparisons showed statistically similar reductions in the risk of 'VTE or VTE-related death for all NOACs. In contrast, reductions in 'major or CRNM bleed' for initial/long-term treatment were significantly better with apixaban compared with all other NOACs, and with dabigatran compared with rivaroxaban and edoxaban. Results from the current analysis indicate that the NOACs offer clinical benefit over conventional therapy while highlighting relative differences in their bleeding profile.

Topics: Administration, Oral; Anticoagulants; Dabigatran; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Time Factors; Treatment Outcome; Venous Thromboembolism

The novel oral anticoagulants (NOAC) dabigatran, apixaban, edoxaban and rivaroxaban target either thrombin or factor Xa for the prevention and treatment of thrombosis. A short introduction of the main indications for an oral anticoagulation is followed by the pharmacology of each drug, their effectiveness, selected drug-drug interactions and adverse drug events, especially bleeding. The article represents clinical aspects for the perioperative management, the possibilities for monitoring of each drug, the application in patients with renal impairment as well as different advantages and disadvantages.

Topics: Administration, Oral; Anticoagulants; Dabigatran; Humans; Perioperative Care; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thrombosis

Regarding anticoagulant therapies there has been a remarkable shift in recent years. The objective of this brief overview is to provide relevant information and guidelines on the advantages and disadvantages of novel anticoagulants addressing specifically the surgical disciplines. Hitherto, conventional anticoagulant therapy in patients with a high thrombosis risk was largely limited to heparins and vitamin-K antagonists (VKA). Their modes of action, the difficulties in managing VKAs (e.g., bridging therapy) and the risk of HIT (heparin-induced thrombocytopenia) associated with heparins are briefly discussed. Novel anticoagulants supposedly eliminate these obstacles. Fondaparinux (Arixtra®) is a fully synthetic pentasaccharide which acts like a heparin but has an increased half life. Fondaparinux has a diminished risk of HIT. However, no specific antidote is currently available for Fondaparinux. The novel oral anticoagulants (NOAC) dabigatran etexilat (Pradaxa®), rivaroxaban (Xarelto®) and apixaban (Eliquis®), also known as "direct" anticoagulants, act independently from antithrombin by inhibiting thrombin, as in the case of dabigatran, or by inhibiting factor Xa, as in the case of rivaroxaban and apixaban. It is assumed that they are suitable for long-term use and do not require laboratory monitoring. Nevertheless, clinical experience is very limited and caution rather than quick conclusions is necessary. Two major drawbacks are on the one hand the risk of drug accumulation in kidney and/or liver disease and, on the other hand, the lack of specific antidotes. In addition, interactions with other medication may have unexpected effects on serum drug levels. Therefore, the analysis of drug levels in the plasma may become necessary in subgroups of patients.. Studies establishing clear recommendations for the desirable and measurable reference range are needed. Similarly, evidence-based recommendations regarding perioperative prevention of thrombosis are required ("bridging": yes or no?). Irrespective of these issues, the authors predict a further expansion of the use of NOACs.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; Blood Coagulation Tests; Dabigatran; Drug Interactions; Factor Xa Inhibitors; Fondaparinux; Heparin; Humans; International Normalized Ratio; Liver Failure; Metabolic Clearance Rate; Morpholines; Perioperative Care; Polysaccharides; Pyrazoles; Pyridines; Pyridones; Renal Insufficiency; Rivaroxaban; Thiophenes; Thrombocytopenia; Thrombosis; Vitamin K

Heart failure (HF) and atrial fibrillation (AF) frequently coexist and share a reciprocal relationship. The presence of AF increases the propensity to HF and can worsen its severity as well as escalating the risk of stroke. Despite the proven efficacy of vitamin K antagonists and warfarin for stroke prevention in AF, their use is beset by numerous problems. These include their slow onset and offset of action, unpredictability of response, the need for frequent coagulant monitoring and serious concerns around the increased risks of intracranial and major bleeding. Three recently approved novel anticoagulants (dabigatran, rivaroxaban and apixaban) are already challenging warfarin use in AF. They have a predictable therapeutic response and a wide therapeutic range and do not necessitate coagulation monitoring. In this article, the relationship between HF and AF and the mechanisms for their compounded stroke risk are reviewed. The evidence to support the use of these three NOACs amongst patients with AF and HF is further explored.

Topics: Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Chronic Disease; Dabigatran; Drug Monitoring; Heart Failure; Hemorrhage; Humans; Morpholines; Outcome Assessment, Health Care; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Severity of Illness Index; Stroke; Thiophenes; Warfarin

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; Dabigatran; Elective Surgical Procedures; Emergencies; Factor Xa Inhibitors; Hemorrhage; Humans; Kidney Diseases; Morpholines; Orthopedic Procedures; Postoperative Complications; Premedication; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Risk; Rivaroxaban; Thiophenes; Thrombophilia; Vitamin K

Pharmacogenetics-guided warfarin dosing is an alternative to standard clinical algorithms and new oral anticoagulants for patients with nonvalvular atrial fibrillation. However, clinical evidence for pharmacogenetics-guided warfarin dosing is limited to intermediary outcomes, and consequently, there is a lack of information on the cost-effectiveness of anticoagulation treatment options. A clinical trial simulation of S-warfarin was used to predict times within therapeutic range for different dosing algorithms. Relative risks of clinical events, obtained from a meta-analysis of trials linking times within therapeutic range with outcomes, served as inputs to an economic analysis. Neither dabigatran nor rivaroxaban were cost-effective options. Along the cost-effectiveness frontier, in relation to clinically dosed warfarin, pharmacogenetics-guided warfarin and apixaban had incremental cost-effectiveness ratios of £13,226 and £20,671 per quality-adjusted life year gained, respectively. On the basis of our simulations, apixaban appears to be the most cost-effective treatment.

Topics: Algorithms; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cost-Benefit Analysis; Dabigatran; Drug Costs; Drug Dosage Calculations; Humans; Morpholines; Pharmacogenetics; Pyrazoles; Pyridones; Quality-Adjusted Life Years; Rivaroxaban; Stroke; Thiophenes; Warfarin

During recent years, three new anticoagulants (dabigatran, rivaroxaban and apixaban) have been introduced to the market, probably with one more anticoagulant (edoxaban) in the next 2 years. This review is not intended to compare the efficacy and risks of these new agents, but rather to detail the advantages and limitations. The pharmacokinetic characteristics of these drugs have few drug and food interactions, predictable dose responses, and rapid onset and offset, thus resulting in simplified management of the patient requiring anticoagulant therapy. No routine laboratory monitoring is required. A somewhat unexpected, but exciting observation involving the new anticoagulants, is the uniform reduction in intracranial bleeding by one-half compared with warfarin. The potential limitations of the new anticoagulants include uncertainty regarding assessment of drug levels, safe drug levels for major surgery, management of major bleeding, renal dependence, multiple dose regimens, adherence in the absence of frequent monitoring and unknown, rare side effects that were not captured in the trials. This review should clarify some of these concerns.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Blood Coagulation; Dabigatran; Disease Management; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Factor Xa Inhibitors; Humans; Intracranial Hemorrhages; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Thromboembolism

Novel oral anticoagulants provide an effective and convenient alternative to warfarin for stroke prevention in patients with atrial fibrillation. However, novel anticoagulants also present new challenges for stroke physicians, such as measurement of anticoagulant effect in emergency situations, use of thrombolysis in acute ischemic stroke, optimal timing of introduction of novel anticoagulants following acute ischemic stroke, and management of intracerebral hemorrhage. In this review, we propose pragmatic approaches to dealing with challenging management issues that will face stroke physicians who care for patients with acute stroke in the novel oral anticoagulant era.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; Child; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiophenes

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

Anticoagulation is important in the management of cardiovascular disorders; however, traditional anticoagulants such as heparins and vitamin K antagonists (VKAs) have limitations, including parenteral administration with the former and the need for coagulation monitoring and dose adjustments with the latter. Three non-VKA oral anticoagulants (OACs), dabigatran, rivaroxaban and apixaban, are available for the prevention of stroke in patients with atrial fibrillation (AF) and may change clinical practice. This article reviews current knowledge and important unanswered questions on the use of these agents in patients with cardiovascular disease.. A literature search was performed using PubMed and the search terms dabigatran, rivaroxaban, apixaban, AF and acute coronary syndrome (ACS). Peer-reviewed, published clinical trials, review articles, relevant treatment guidelines and prescribing information documents were identified and reviewed for relevance.. Dabigatran is an oral direct thrombin inhibitor; rivaroxaban and apixaban are oral direct Factor Xa inhibitors. These agents have a quicker onset and offset of action, more predictable pharmacokinetic and pharmacodynamic profiles, and fewer drug-drug interactions than VKAs, allowing use of fixed doses. For the prevention of stroke in patients with AF, the non-VKA OACs were either non-inferior or superior to warfarin with similar or improved bleeding profiles, particularly with respect to reductions in intracranial haemorrhage. In patients with ACS receiving dual antiplatelet therapy, the addition of rivaroxaban significantly reduced the rate of death from cardiovascular causes, myocardial infarction or stroke without increasing fatal bleeding, but led to higher rates of major bleeding. Dose reductions with non-VKA OACs are mandated in certain circumstances in patients with AF, such as moderate renal impairment. Contraindications include creatinine clearance <15 mL/min (<30 mL/min for dabigatran in Europe and Canada) and moderate or severe hepatic impairment, but patients can be transitioned to other anticoagulants if appropriate. It is unknown which non-VKA OAC is optimal for stroke prevention in patients with AF, although factors such as co-medications (e.g. dabigatran may be preferred if a patient is taking a co-medication that is a strong cytochrome P450 3A4 inhibitor) and renal function (rivaroxaban and apixaban depend less on renal clearance than dabigatran) will be important for individual patients. Addition of rivaroxaban to antiplatelet therapy for prevention of recurrent events in patients with recent ACS is approved in Europe for patients at the highest risk (with elevated cardiac biomarkers) and must take into account the increased risk of major bleeding. Although routine coagulation monitoring is not required, an understanding of which assays are appropriate for each non-VKA OAC and how they are affected is important. In a bleeding emergency, non-specific prohaemostatic agents are suggested to reverse the action of the non-VKA OACs, but more clinical data are needed.. Non-VKA OACs provide similar or improved efficacy and, on current evidence, improved safety. They provide greater convenience, compared with traditional anticoagulants for the prevention of stroke in patients with AF. Rivaroxaban may be of benefit to selected high-risk patients with ACS. Selection of the most appropriate non-VKA OAC will depend on individual patient factors.

Topics: Administration, Oral; Animals; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cardiovascular Diseases; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes

In October 2011, DTB reviewed the use of dabigatran, the first new oral anticoagulant licensed for the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (AF) and one or more defined risk factors.1 We noted that the potential advantages of dabigatran for many patients with AF and the continuing need to provide warfarin therapy for others, provided an important challenge for the NHS. The use of dabigatran has increased significantly in the UK and two other drugs have been licensed for this indication (▾apixaban-Eliquis, Bristol-Myers Squibb/Pfizer; ▾rivaroxaban-Xarelto, Bayer plc).2-6 In addition, published drug safety alerts have highlighted the risk of serious haemorrhage associated with the use of these drugs.7-9 Here we review the evidence for apixaban and rivaroxaban for the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation.

Topics: Adult; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Embolism; Factor Xa Inhibitors; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes

Although highly effective, warfarin use is complicated by its unpredictable narrow therapeutic window, genetic heterogeneity in pharmacokinetic response, numerous food and drug interactions, and the need for regular international normalized ratio (INR) monitoring. Currently, several novel oral anticoagulant (NOAC) drugs (dabigatran, rivaroxaban, apixaban) are available on the market as alternatives to warfarin. These agents all feature more predictable pharmacodynamic and pharmacokinetic properties than warfarin. Additionally, the NOACs do not require routine monitoring of coagulation parameters, and have a relatively lower potential for interactions with drug, herb, and dietary constituents, which enhances the convenience of management for both patients and health professionals alike. However, there are other considerations regarding the use of NOACs that must be taken into account during management of therapy. In contrast to warfarin, most NOACs need dosage adjustments in renal impairment and are contraindicated in severe liver impairment, and there are no specific antidotes for treating NOAC-related over-anticoagulation. The more frequent dosing needed for NOACs may reduce adherence, especially in elderly patients with polypharmacy. Furthermore, NOACs, especially dabigatran, are not as well tolerated as warfarin in patients with gastrointestinal diseases. Overall, the availability of the NOACs has expanded the treatment armamentarium, but they are not without risk. Given the limited experience with the NOACs, their limited range of indications, and their cost, the characteristics of each anticoagulant must be carefully considered to carefully select the agent that will provide the optimal risk/benefit profile in the individual patient.

Topics: Administration, Oral; Aging; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Complementary Therapies; Dabigatran; Drug Interactions; Drug Monitoring; Humans; International Normalized Ratio; Kidney Diseases; Liver Diseases; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Sex Factors; Stroke; Thiophenes; Warfarin

Patients with acute coronary syndrome (ACS) usually receive acetylsalicylic acid plus an adenosine diphosphate (ADP) receptor inhibitor to reduce the long-term risk of recurrent events. However, patients receiving standard antiplatelet prophylaxis still face a substantial risk of recurrent events. Strategies involving 3 antithrombotic agents with different modes of action have now been tested. In Thrombin Receptor Antagonists for Clinical Event Reduction (TRA-CER), compared with standard care alone, bleeding complications including intracranial hemorrhage (ICH) were increased with the addition of vorapaxar, without efficacy benefit. In Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Atherosclerosis (TRA 2°P-TIMI 50), the addition of vorapaxar reduced recurrent events compared with standard care in stable patients with prior myocardial infarction. This study was terminated early in patients with prior stroke owing to excess ICH, though an increased risk of ICH or fatal bleeding was not detected in patients with prior myocardial infarction. The Apixaban for Prevention of Acute Ischemic and Safety Events 2 (APPRAISE-2) trial of standard-dose apixaban added to standard care in patients with ACS was also stopped early owing to excess serious bleeding. However, in Rivaroxaban in Combination With Aspirin Alone or With Aspirin and a Thienopyridine in Patients With Acute Coronary Syndromes (ATLAS ACS 2 TIMI 51), fatal bleeding or fatal ICH did not increase with low-dose rivaroxaban added to low-dose acetylsalicylic acid-based standard care compared with standard care alone. In that trial, a significant reduction of recurrent vascular events was shown with 3 antithrombotic regimens compared with standard care. Therefore, depending on drug dose and patient population, further reductions in recurrent vascular events after ACS may be possible in future clinical practice, with a favorable benefit-risk profile.

Topics: Acute Coronary Syndrome; Anticoagulants; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Coronary Thrombosis; Dabigatran; Hemorrhage; Humans; Imines; Lactones; Morpholines; Platelet Activation; Platelet Aggregation Inhibitors; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Secondary Prevention; Thiophenes; Thrombin

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

Anticoagulation remains the cornerstone of treatment in patients with deep vein thrombosis (DVT). While parenteral anticoagulants and oral vitamin K antagonists (e.g., warfarin) have been used for many decades, the recent development of novel oral anticoagulants have provided clinicians with an expanding set of therapeutic options for DVT. This review summarizes the pharmacology and clinical trial results of these new oral anticoagulants. Several practical considerations to the use of these oral anticoagulants including issues related to adherence, monitoring, and reversal are also discussed.

Topics: Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Humans; Medication Adherence; Morpholines; Patient Selection; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Venous Thrombosis

Antiplatelet and anticoagulant drugs are the mainstay of treatment of acute coronary syndrome (ACS). The last 30 years have seen the development of various agents, a deeper understanding of the pathobiology of this disease, and an evolution in its treatment. We review the role of contemporary agents in ACS and highlight key clinical trials of these agents.

Topics: Acute Coronary Syndrome; Adenosine; Anticoagulants; Aspirin; Benzimidazoles; beta-Alanine; Clopidogrel; Dabigatran; Enoxaparin; Fondaparinux; Heparin; Hirudins; Humans; Morpholines; Peptide Fragments; Piperazines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Polysaccharides; Prasugrel Hydrochloride; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban; Thiophenes; Ticagrelor; Ticlopidine; 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

The recent arrival of the target-specific oral anticoagulants (TSOACs) offers potential advantages in the field of anticoagulation. However, there are no rapid and accurate and routinely available laboratory assays to evaluate their contribution to clinical bleeding. With the expanding clinical indications for the TSOACs, and the arrival of newer reversal agents on the market, the emergency clinician will need to be familiar with drug specifics as well as methods for anticoagulation reversal. This review offers a summary of the literature and some practical strategies for the approach to the patient taking TSOACs and the management of bleeding in these cases.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Benzimidazoles; beta-Alanine; Dabigatran; Emergency Treatment; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes

The best regimen for the long-term management of patients with atrial fibrillation who present with an acute coronary syndrome or require placement of a coronary stent remains unclear. Clinicians need to understand the risk of stroke, stent thrombosis, and major bleeding associated with treating these patients. Numerous studies and risk assessment schemes provide clinicians with an estimation of the risk of stroke, stent thrombosis, and major bleeding that may be associated with the use or avoidance of dual antiplatelet therapy with concurrent anticoagulation therapy (triple therapy). This review discusses the special antithrombotic needs in patients who have atrial fibrillation and either acute coronary syndrome or a requirement for percutaneous coronary intervention, including the published evidence for non-vitamin K oral anticoagulants, and the unanswered questions in this patient population. In conclusion, until the results of additional ongoing or planned randomized trials are known, clinicians must continue to rely on expert opinion and their own clinical judgment when treating these patients.

Topics: Acute Coronary Syndrome; Anticoagulants; Aspirin; Atrial Fibrillation; Clopidogrel; Comorbidity; Drug Therapy, Combination; Factor Xa Inhibitors; Humans; Morpholines; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Stroke; Thiophenes; Thrombosis; Ticlopidine

Topics: Acute Coronary Syndrome; Adenosine; Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Hemorrhage; Humans; Morpholines; Percutaneous Coronary Intervention; Piperazines; Platelet Aggregation Inhibitors; Postoperative Complications; Prasugrel Hydrochloride; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thrombosis; Ticagrelor

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

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

Dabigatran, a direct thrombin inhibitor and 2 factor Xa inhibitors, rivaroxaban and apixaban, are target-specific oral anticoagulants (TSOACs) approved for prevention of stroke or systemic embolism in patients with nonvalvular atrial fibrillation (AF). Published data suggest that all 3 agents are at least as efficacious as dose‑adjusted warfarin in stroke prevention. Because of their greater specificity, rapid onset of action, and predictable pharmacokinetics, TSOACs have some advantages over vitamin K antagonists, which facilitates their use in clinical practice. The current review addresses the practical questions relating to the use of TSOACs in AF patients based on the available data and personal experience. We discuss topics such as patient selection, renal impairment, drug interactions, switching between anticoagulants, laboratory monitoring, and the risk of bleeding along with its management. We will focus on the aspects of the optimization of treatment with TSOACs in stroke prevention. The understanding of these practical issues by clinicians and patients is of key importance for the safe and effective use of TSOACs in everyday practice.

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

There are concerns regarding increased risk of acute coronary syndrome with dabigatran. We aimed to assess whether alternative treatment options such as rivaroxaban or apixaban carry a similar risk as compared with dabigatran.. We searched MEDLINE and EMBASE for randomized controlled trials of apixaban, dabigatran or rivaroxaban against control (placebo, heparin or vitamin K antagonist). We pooled odds ratios (OR) for adverse coronary events (acute coronary syndrome or myocardial infarction) using fixed effect meta-analysis and assessed heterogeneity with I(2) . We conducted adjusted indirect comparisons to compare risk of adverse coronary events with apixaban or rivaroxaban vs. dabigatran.. Twenty-seven randomized controlled trials met the inclusion criteria. Dabigatran was associated with a significantly increased risk of adverse coronary events in pooled analysis of nine trials (OR 1.45, 95% CI 1.14, 1.86). There was no signal for coronary risk with apixaban from nine trials (pooled OR 0.89, 95% CI 0.78, 1.03) or rivaroxaban from nine trials (pooled OR 0.81, 95% CI 0.72, 0.93). Overall, adjusted indirect comparison suggested that both apixaban (OR 0.61, 95% CI 0.44, 0.85) and rivaroxaban (OR 0.54; 95% CI 0.39, 0.76) were associated with lower coronary risk than dabigatran. Restricting the indirect comparison to a vitamin K antagonist as a common control, yielded similar findings, OR 0.57 (95% CI 0.39, 0.85) for apixaban vs. dabigatran and 0.53 (95% CI 0.37, 0.77) for rivaroxaban vs. dabigatran.. There are significant differences in the comparative safety of apixaban, rivaroxaban and dabigatran with regards to acute coronary adverse events.

Topics: Acute Coronary Syndrome; Antithrombins; Benzimidazoles; beta-Alanine; Dabigatran; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiophenes

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

Despite widespread adoption of acetylsalicylic acid and P2Y12 receptor inhibitor therapy as the standard of care for secondary event prevention in patients with acute coronary syndrome (ACS), the rate of cardiovascular death or myocardial infarction following discharge is approximately 24-31% over five years, indicating an important unmet need to reduce further the risk of recurrent ACS events. Because thrombin has a role in arterial thrombus generation, a mechanistic rationale exists for adding an anticoagulant to dual antiplatelet therapy to reduce cardiovascular event rates and mortality. The direct thrombin inhibitor dabigatran and the direct Factor Xa inhibitors rivaroxaban and apixaban have been investigated for this application, with only rivaroxaban successfully completing a phase III trial. These results suggest that dose selection is of paramount importance in this indication, with lower anticoagulant doses (relative to those used in other indications, such as stroke prevention in atrial fibrillation) plus low-dose acetylsalicylic acid potentially improving cardiovascular outcomes. This article reviews clinical trial data of anticoagulants for secondary event prevention in patients with ACS; it also discusses the mechanistic reasons that may underlie these observations and looks towards the potential impact of findings from the ATLAS ACS 2 TIMI 51 trial on clinical practice.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Azepines; Azetidines; Benzamides; Benzimidazoles; Benzylamines; beta-Alanine; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thrombin; Vitamin K

Anticoagulation therapy is one of the most important advances in modern medicine, saving thousands of lives from the complications of atrial fibrillation and mechanical heart valves and preventing recurrent venous thromboembolism. Warfarin and heparins have been the predominant anticoagulants used until the past decade. However, the arrival of newer target-specific anticoagulants has brought us easier and equally effective agents, although no specific antidotes are yet available. Being relatively newer drugs, physicians need to be familiar with the various practical issues that may be encountered with the prescription of these drugs, which are summarised in this review.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Venous Thromboembolism; Warfarin

New oral anticoagulants like the direct thrombin inhibitor, dabigatran (Pradaxa®), and factor Xa-inhibitors, rivaroxaban (Xarelto®) and apixaban (Eliquis®) are available for prophylaxis and treatment of thromboembolic disease. They are emerging alternatives to warfarin and provide equal or better clinical outcome together with reduced need for routine monitoring. Methods for measuring drug concentrations are available, although a correlation between plasma drug concentrations and the risk of bleeding has not been firmly established. Standard laboratory measures like prothrombin time and activated partial thromboplastin time are not sensitive enough to detect thrombin or factor Xa inhibition provided by new oral anticoagulants. Thus, these standard tests may only be used as a crude estimation of the actual anticoagulation status. Further challenges regarding patients receiving new oral anticoagulants who presents with major bleeding or need for emergency surgery pose a unique problem. No established agents are clinically available to reverse the anticoagulant effect, although preclinical data report prothrombin complex concentrate as more efficient than fresh frozen plasma or other prohaemostatic agents. This review summaries current knowledge on approved new oral anticoagulants and discusses clinical aspects of monitoring, with particular focus on the management of the bleeding patient.

Topics: Anticoagulants; Benzimidazoles; beta-Alanine; Blood Coagulation Tests; Dabigatran; Drug Monitoring; Factor Xa Inhibitors; Hemorrhage; Hemostatic Techniques; Hemostatics; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thrombin; Thromboembolism; Thrombophilia

Atrial fibrillation increases the risk of stroke, which is a leading cause of death and disability worldwide. The use of oral anticoagulation in patients with atrial fibrillation at moderate or high risk of stroke, estimated by established criteria, improves outcomes. However, to ensure that the benefits exceed the risks of bleeding, appropriate patient selection is essential. Vitamin K antagonism has been the mainstay of treatment; however, newer drugs with novel mechanisms are also available. These novel oral anticoagulants (direct thrombin inhibitors and factor Xa inhibitors) obviate many of warfarin's shortcomings, and they have demonstrated safety and efficacy in large randomized trials of patients with non-valvular atrial fibrillation. However, the management of patients taking warfarin or novel agents remains a clinical challenge. There are several important considerations when selecting anticoagulant therapy for patients with atrial fibrillation. This review will discuss the rationale for anticoagulation in patients with atrial fibrillation; risk stratification for treatment; available agents; the appropriate implementation of these agents; and additional, specific clinical considerations for treatment.

Topics: Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Hemorrhage; Humans; Medication Adherence; Morpholines; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Stroke; Thiophenes; Warfarin

The use of oral anticoagulants is increasing because of the rising prevalence of atrial fibrillation and other cardiovascular diseases that occur in an aging population. In the last decade, several new oral anticoagulants have emerged, comprising the direct thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban and rivaroxaban. Although these new anticoagulants may not affect clear corneal cataract surgery, their use will impact the management of patients having eyelid, orbital, and nasolacrimal procedures. The objective of this review is to provide a concise and practical approach to the perioperative management of patients who require an oculoplastic procedure and are receiving these new anticoagulants.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Cardiovascular Diseases; Cataract Extraction; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Surgery, Plastic; Thiophenes

The acceptability of warfarin has been limited by mandatory laboratory monitoring. A number of new orally active anticoagulants (NOACs), which can be used as alternatives to warfarin, are now available.. We review the clinical indications and considerations associated with the use of the NOACs.. The NOACs currently approved in Australia are dabigatran, rivaroxaban and apixaban. Indications include thromboprophylaxis in non-valvular atrial fibrillation and following hip and knee replacement surgery. Rivaroxaban is also approved for treatment and secondary prevention of deep venous thrombosis (DVT) and pulmonary embolus (PE). The NOACs differ from warfarin in that they do not require laboratory monitoring. They need to be used cautiously in patients with renal impairment and are contraindicated in patients with renal failure. Bleeding may require blood product replacement aided by haematological advice and specialist investigations. Antidotes to the NOACS are undergoing clinical trials.

Topics: Anticoagulants; Antithrombins; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Blood Coagulation Tests; Dabigatran; Drug Monitoring; Factor Xa Inhibitors; General Practice; Hemorrhage; Humans; Kidney; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism; Warfarin

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

Atrial fibrillation (AF) confers a 4.5% risk of stroke per year. The risk of stroke increases with various risk factors and until recently, warfarin has been the gold standard of thromboembolism prophylaxis in AF for many years. The dosage of warfarin requires regular adjustment dependent on the INR, to keep within a narrow therapeutic range of 2.0- 3.0. The INR can be altered by concomitant drugs, foods and alcohol and requires inconvenient blood monitoring. Underanticoagulation places patients at risk of stroke, whilst over-anticoagulation confers significant bleeding risk. Consequently approximately half who would benefit from oral anticoagulation do not have it prescribed. Novel oral anticoagulants with predictable pharmacokinetics and improved efficacy and safety profiles are currently being developed for stroke prevention in AF. Three novel oral anticoagulants have just completed Phase III trials for stroke prevention, all with impressive results; the direct thrombin inhibitor, dabigatran and the oral factor Xa inhibitors, rivaroxaban and apixaban.

Topics: Administration, Oral; Age Factors; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Brain Ischemia; Clinical Trials, Phase III as Topic; Dabigatran; Humans; Morpholines; Practice Guidelines as Topic; Primary Prevention; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Stroke; Thiophenes

Hospitalized medical and surgical patients encompass a group of patients in whom venous thromboembolism (VTE) poses a major concern on morbidity and mortality. Recently, direct oral anticoagulants for the prevention of VTE have been developed to overcome the drawbacks of the food/drug interactions and the need for frequent laboratory monitoring and dose adjustments associated with the use of vitamin K antagonists and the inconvenience of the subcutaneous administration of low-molecular-weight heparins and fondaparinux. The novel oral anticoagulants that have been tested in major clinical trials for VTE prevention in medical and surgical patients are the thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban, rivaroxaban, and edoxaban, which will be the focus of this review. While the new drugs proved to be highly effective and safe in the prevention of VTE following major orthopedic surgery, they failed to show a favorable benefit-to-risk profile in hospitalized medical patients receiving extended anticoagulation beyond the hospital stay.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Half-Life; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Venous Thromboembolism; Vitamin K

For decades the antithrombotic management of venous thromboembolism (VTE) was limited to parenteral heparin formulations and oral vitamin K antagonists. Even though both classes of anticoagulants are effective, they have several limitations, including a narrow therapeutic window and the need to monitor anticoagulant activity. Direct oral anticoagulants (DOACs) that specifically target factor IIa or Xa have emerged. Recent data suggest that they are at least as effective and as safe as conventional therapy and have practical advantages, such as fixed dose regimen and no need for laboratory monitoring. Hence, they represent a major step forward in the acute treatment and long-term prevention of VTE. In this review, we outline the use of DOACs in the management of VTE and provide an overview of recently published major trials.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Humans; Morpholines; Neoplasms; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Venous Thromboembolism

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

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

The new oral anticoagulants (NOACs), which include dabigatran, rivaroxaban, apixaban, and edoxaban, are poised to replace warfarin for treatment of the majority of patients with venous thromboembolism (VTE). With a rapid onset of action and the capacity to be administered in fixed doses without routine coagulation monitoring, NOACs streamline VTE treatment. In phase 3 trials in patients with acute symptomatic VTE, NOACs have been shown to be noninferior to conventional anticoagulant therapy for prevention of recurrence and are associated with less bleeding. Rivaroxaban and dabigatran are already licensed for VTE treatment in the United States, and apixaban and edoxaban are under regulatory consideration for this indication. As the number of approved drugs increases, clinicians will need to choose the right anticoagulant for the right VTE patient. To help with this decision, this review (1) compares the pharmacologic profiles of the NOACs, (2) outlines the unique design features of the phase 3 trials that evaluated the NOACs for VTE treatment, (3) reviews the results of these trials highlighting similarities and differences in the findings, (4) provides perspective about which VTE patients should receive conventional treatment or are candidates for NOACs, and (5) offers suggestions about how to choose among the NOACs.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Drug Therapy; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Treatment Outcome; Venous Thromboembolism

Topics: Administration, Oral; Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cerebral Hemorrhage; Dabigatran; Gastrointestinal Hemorrhage; Humans; Intracranial Embolism; Morpholines; Postoperative Complications; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Thiophenes; Thrombosis; Vitamin K; Warfarin

New oral anticoagulants (NOACs) have emerged as an alternative therapy to warfarin in the treatment of arterial and venous thromboembolism and in stroke prevention in patients with non-valvular atrial fibrillation (AF). Three of them, i.e., dabigatran, rivaroxaban, and apixaban, have been approved for clinical use in North America and in a number of European countries. In non-valvular AF, their approval was based on large randomized trials showing that they are non-inferior or even, in some instances, superior to warfarin. Dabigatran is a direct thrombin (factor IIa) inhibitor; rivaroxaban and apixaban are direct factor Xa inhibitors. Before using NOACs, it is recommended to become familiar with their pharmacological characteristics and their metabolism. The absence of specific antidotes is often cited as part of the possible weaknesses of NOACs. Antidotes are perceived to be useful in emergency situations such as life-threatening bleeding or non-elective major surgery. NOACs do not require blood monitoring, and therefore, patient compliance to the treatment is essential. For the present time, there are no specific antidotes available for the three NOACs approved for clinical use. However, phase I or phase II research studies in this area are ongoing. For dabigatran, a specific antidote has been tested in a rat model of anticoagulation, and a study in healthy male volunteers has been recently reported. For rivaroxaban, prothrombin complex concentrates (PCCs) have been found to completely reverse the prolongation of the prothrombin time induced by this NOAC. For apixaban, recombinant factor VII was found in an experimental study using human blood to be superior to activated PCC (aPCC) and PCC. More specific antidotes for rivaroxaban and apixaban are in phases I and II evaluation. The management of patients suffering from a major bleeding or requiring a non-elective major surgery includes non-specific reversal agents and is discussed in the light of a recent position paper and of current literature. Most recommendations are based on expert opinions only as randomized trials using agents for reversal of anticoagulation in case of life-threatening bleeding or of major urgent surgery are not available.

Topics: Animals; Antidotes; Antithrombins; Benzimidazoles; beta-Alanine; Blood Coagulation; Dabigatran; Elective Surgical Procedures; Factor Xa Inhibitors; Hemorrhage; Hemostatics; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Venous Thromboembolism

The aim was to perform a review of the efficacy and safety of new oral anticoagulants (NOAs) in the management of venous thromboembolism (VTE).. This was a systematic review and meta-analysis. On March 26, 2014, Medline, Embase, and the Cochrane trial register were searched for randomized controlled trials (RCTs) comparing the NOAs dabigatran, rivaroxaban, apixaban, and edoxaban with vitamin K antagonists (VKAs) in VTE treatment and secondary prevention. Two investigators assessed the methodological quality of the RCTs. The main study outcomes (efficacy, safety and net clinical benefit) were expressed as risk ratios (RR) with 95% confidence interval (CI).. Ten RCTs, mostly with low risk of bias, with nearly 38,000 patients, were identified. In six trials of treatment, NOAs were equally effective as VKAs in preventing recurrent symptomatic VTE (RR 0.89, 95% CI 0.75-1.05), but major bleeding occurred less often (1.08% vs. 1.73% for VKAs, RR 0.63, 95% CI 0.51-0.77), leading net clinical benefit to favor NOAs (RR 0.79, 95% CI 0.70-0.90). Fatal bleeding occurred less often with NOAs (0.09% vs. 0.18% for VKAs), a difference that approached statistical significance (RR 0.51, 95% CI 0.26-1.01). In three secondary prevention trials, NOAs reduced VTE recurrence rates to 1.32% (vs. 7.24% with placebo, RR 0.17, 95% CI 0.12-0.24) and fatal pulmonary embolism (PE) (including unexplained deaths) to 0.1% (vs. 0.29% for placebo, RR 0.37, 95% CI 0.10-1.38) at the expense of clinically relevant non-major bleeding (4.3% vs. 1.8% for placebo, RR 2.32, 95% CI 1.65-3.35), but not major bleeding. All-cause mortality rate was reduced to 0.41% with NOAs (vs. 0.86% with placebo, RR 0.38, 95% CI 0.18-0.79). Net clinical benefit favored NOAs (RR 0.21, 95% CI 0.15-0.29), and NNT was 18.. Compared to VKAs, NOAs are not only effective in treating VTE but also safer in terms of bleeding, thereby conferring clinical benefit. Their safety and efficacy was confirmed further in secondary prevention trials.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Clinical Trials, Phase III as Topic; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Secondary Prevention; Thiazoles; Thiophenes; 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

For the first time in 50 years new oral anticoagulants of proven efficacy and with acceptable safety profiles are available for patients with atrial fibrillation and venous thromboembolism. Here is a brief overview of the benefits and possible disadvantages of using these drugs.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes

To systematically examine discontinuation rates with new US Food and Drug Administration-approved oral anticoagulants (NOACs) in patients with various indications for long-term anticoagulation.. Poor adherence to medications is considered a potential and frequent cause of treatment failure. We searched the PubMed, Cochrane Central Register of Controlled Trials, EMBASE, EBSCO, Web of Science, and CINAHL databases for articles published from January 1, 2001, through September 15, 2013. The following Medical Subject Heading terms and/or keywords were used for our database searches: rivaroxaban, dabigatran, apixaban, new oral anticoagulants, oral thrombin inhibitors, and oral factor Xa inhibitors. Articles in English that focused on randomized controlled trials (RCTs) comparing NOACs (apixaban, dabigatran, and rivaroxaban) with conventional therapy or placebo were abstracted. Independent extraction of relevant data was performed by 2 authors. The primary end point of interest was discontinuation due to all causes. Other end points of interest were discontinuation due to adverse events, consent withdrawal, and nonadherence.. Eighteen RCTs including a total of 101,801 patients were included for analysis. Total study drug discontinuation rates were not statistically different with NOACs in comparison to pharmacologically active comparators for treatment of venous thromboembolism/pulmonary embolism (risk ratio [RR], 0.91; 95% CI, 0.74-1.13; P=.40) and for NOACs in comparison to warfarin and aspirin for prevention of stroke in patients with atrial fibrillation (RR, 1.01; 95% CI, 0.87-1.17; P=.92). In contrast, in acute coronary syndromes, total study drug discontinuation with NOACs was significantly higher than with placebo (RR, 1.40; 95% CI, 1.07-1.83; P=.01). Overall discontinuations were comparable to those with active comparators.. Study drug discontinuations with NOACs were not significantly different from those with conventional drugs in treatment of venous thromboembolism/pulmonary embolism and prevention of stroke in patients with atrial fibrillation but were worse in acute coronary syndromes as noted in evidence from contemporary RCTs.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Humans; Medication Adherence; Morpholines; Pulmonary Embolism; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Venous Thromboembolism

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

The prevalence and incidence of atrial fibrillation (AF) are increasing rapidly. Key recommendations in management of AF include prompt administration of oral anticoagulation to all patients with elevated risk of thromboembolic complications, proper use of antiarrhythmic drugs and invasive therapies in highly symptomatic patients and adequate rate control in patients with permanent AF. The selection between warfarin and the novel oral anticoagulants (apixaban, dabigatran, rivaroxaban) is based on careful evaluation of the benefits and disadvantages of the drugs in a given patient.

Topics: Administration, Oral; Anti-Arrhythmia Agents; Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Humans; Incidence; Morpholines; Practice Guidelines as Topic; Prevalence; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Warfarin

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

Many new oral anticoagulants (NOACs; dabigatran, rivaroxaban, and apixaban) are currently available to treat thromboembolic disease. There are no head-to-head trials comparing these agents. To assess the efficacy and safety of NOACs for prevention of recurrent venous thromboembolism (VTE), we performed a network meta-analysis.. Medline, Embase, and the Cochrane-controlled trial register were searched, without language restriction, to identify trials. Studies were evaluated according to a priori inclusion criteria and appraised using established internal validity criteria. Adjusted indirect comparisons between agents were performed using well-established methods.. Three trials meeting inclusion criteria were identified. Direct comparison between apixaban 2.5 mg twice daily (BID) versus apixaban 5 mg BID showed no difference for any outcome. Clinically relevant non-major bleeding occurred less with both apixaban 2.5 mg BID (OR 0.23, 95% CI 0.08-0.62, P=0.004) and apixaban 5 mg BID [OR 0.31, 95% CI 0.11-0.82, P=0.019] compared to rivaroxaban 20 mg daily. Apixaban 2.5 mg BID showed less clinically relevant non-major bleeding than dabigatran 150 mg BID [OR 0.4, 95% CI 0.16-0.9, P=0.04], but not apixaban 5 mg BID. There were no differences between rivaroxaban 20 mg daily and dabigatran 150 mg BID. No differences in risk for recurrent VTE, major bleeding, or mortality were observed for any comparison between any pair of NOACs.. There were no significant differences in risk for recurrent VTE, major bleeding, or all-cause mortality between the NOACs. However, apixaban 2.5 mg BID was associated with less clinically significant non-major bleeding than either rivaroxaban 20 mg daily or dabigatran 150 mg BID.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Chi-Square Distribution; Dabigatran; Hemorrhage; Humans; Morpholines; Odds Ratio; Pyrazoles; Pyridones; Recurrence; Risk Assessment; Risk Factors; Rivaroxaban; Thiophenes; Time Factors; Treatment Outcome; Venous Thromboembolism

Recent reports suggest altered antithrombotic efficacy and higher risk of bleeding with new oral anticoagulants (NOACs) in patients with renal insufficiency. A meta-analysis was performed to evaluate the efficacy and safety with recommended doses of NOAC compared with conventional treatment in patients with renal insufficiency.. PubMed, Cochrane Library, EMBASE, EBSCO, Web of Science, and CINAHL databases were searched from January 1, 2001 through March 23, 2014. Randomized controlled trials that compared NOACs (rivaroxaban, apixaban, and dabigatran) with comparators (vitamin K antagonist/warfarin, low molecular weight heparin, aspirin, placebo) were selected. We defined moderate renal insufficiency as creatinine clearance (estimated glomerular filtration rate [eGFR]) of 30-49 mL/min, and mild renal insufficiency as eGFR 50-79 mL/min.. There were 40,693 patients with renal insufficiency in 10 trials. Compared with other anticoagulants in patients with mild renal insufficiency there was significantly less major or clinically relevant nonmajor bleeding (odds ratio [OR], 0.81; 95% confidence interval [CI], 0.72-0.90) and stroke or systemic embolism (OR, 0.70; 95% CI, 0.54-0.92) with NOACs. Using random effects meta-analysis, there was significantly less stroke or systemic embolism (OR, 0.72; 95% CI, 0.57-0.92) and a trend toward less major or clinically relevant nonmajor bleeding (OR, 0.82; 95% CI, 0.59-1.14) with the NOACs among patients with moderate renal insufficiency, and this became statistically significant when evaluated using a fixed effects model. NOACs showed efficiency comparable with conventional anticoagulants for prevention of venous thromboembolism or related mortality.. In patients with renal insufficiency, recommended doses of novel anticoagulants are noninferior and relatively safe compared with conventional anticoagulants.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Renal Insufficiency; Rivaroxaban; Stroke; Thiophenes; Thromboembolism

Warfarin, a vitamin K antagonist, is the most widely used oral anticoagulant in the world. It is cheap and effective, but its use is limited in many patients by unpredictable levels of anticoagulation, which increases the risk of thromboembolic or haemorrhagic complications. It also requires regular blood monitoring and dose adjustment. New classes of drugs, non-vitamin K antagonist oral anticoagulants (NOACs), are now supported as alternatives to warfarin. Three NOACs are licensed: dabigatran, a direct thrombin inhibitor, and rivaroxaban and apixaban, antagonists of factor Xa. NOACs do not require routine blood monitoring or dose adjustment. They have a rapid onset and offset of action and fewer food and drug interactions. Current indications include treatment and prophylaxis of venous thromboembolism and prevention of cardioembolic disease in non-valvular atrial fibrillation. Effective antidotes are lacking and some caution must be used in severe renal impairment, but favourable trial evidence has led to their widespread adoption. Research is ongoing, and an increase in their use and indications is expected in the coming years.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Cost-Benefit Analysis; Dabigatran; Drug Administration Schedule; Evidence-Based Medicine; Factor Xa Inhibitors; Humans; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Venous Thromboembolism; Vitamin K; Warfarin

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

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

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

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

Target-specific oral anticoagulants (apixaban, rivaroxaban, and dabigatran) are widely available for the treatment of venous thromboembolism (VTE). Although analyses comparing these agents to placebo or warfarin exist, direct comparisons of these agents for extended VTE treatment have not been conducted. Therefore, this network meta-analysis aimed to evaluate the efficacy and tolerability of VKA and target-specific oral anticoagulants for extended VTE treatment using a mixed-treatment comparison, meta-analytic approach.. A comprehensive literature search of EMBASE and MEDLINE was conducted to identify relevant randomized, controlled trials published in English between 1960 and November 2013. Eligible studies investigated the extended use (≥6 months) of oral anticoagulants (apixaban, dabigatran, rivaroxaban, and/or warfarin [conventional or low dose]) and placebo in patients with confirmed VTE. Search terms included extension or extended treatment or therapy, venous thromboembolism (or VTE), deep vein thrombosis (or DVT), pulmonary embolism (or PE), and anticoagulant or anticoagulant agent. Key articles were cross-referenced for additional studies. The efficacy end points evaluated were recurrent VTE or death from any cause, DVT, and nonfatal pulmonary embolism PE. Tolerability end points included major bleeding and nonmajor or clinically relevant bleeding. The data were screened, evaluated, and entered into statistical software to generate direct and indirect comparisons of the various anticoagulants across each study. The data are reported as rate ratios and 95% credible intervals.. Ten trials were analyzed and aggregated, representing data from >14,000 patients. With respect to efficacy end points, no statistically significant between-treatment differences in the composite end point of VTE or death, nonfatal PE, or DVT were found. Major bleeding was significantly greater with warfarin versus apixaban (rate ratio, 4.24; credible interval, 1.28-25.0), and the risk for major bleeding varied somewhat with warfarin and greatly with rivaroxaban. The assessment of nonmajor or clinically relevant bleeding did not identify any meaningful differences between these agents.. The majority of the data represented in this study were derived from noninferiority trials. In the present meta-analysis, efficacy end points in the extended treatment of VTE with apixaban, dabigatran, rivaroxaban, warfarin (conventional and low dose), and placebo were not significantly different. Elevated bleeding risks were identified with rivaroxaban and warfarin; however, the wide credible intervals with rivaroxaban prevent the interpretation of these increased risks.

Topics: Administration, Oral; Anticoagulants; Dabigatran; Hemorrhage; Humans; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Venous Thromboembolism; Warfarin

The approval of the oral direct thrombin inhibitor dabigatranetexilat and the oral factor Xa inhibitors rivaroxaban and apixaban as thromboprophylaxis challenges the position of the vitamin K antagonists (VKA). Predictable pharmacodynamics gives the new oral anticoagulants an advantageous profile. Unlike VKAs there is no specific reversal agent available for the new oral anticoagulants. Experience with haemostatic products for the emergency management of critical bleeding caused by these agents is limited.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Blood Coagulation Factors; Blood Coagulation Tests; Dabigatran; Drug Monitoring; Factor Xa Inhibitors; Hemorrhage; Humans; Plasma; Pyrazoles; Pyridones; Rivaroxaban; Vitamin K

Topics: Anticoagulants; Antidotes; Benzimidazoles; beta-Alanine; Dabigatran; Emergencies; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Surgical Procedures, Operative; Thiophenes; Wounds and Injuries

New oral anticoagulants (NOACs) are increasingly replacing vitamin K antagonists and older parenteral agents in clinical practice. NOACs offer several advantages compared with standard agents, including rapid onset of action, fixed dosing, and no requirement for routine coagulation monitoring. However, like all anticoagulants, NOACs carry a risk of bleeding. Here, we discuss the pharmacology and safety of NOACs, with particular emphasis on the risks of bleeding associated with NOACs versus standard anticoagulants, and we provide an overview of current bleeding management strategies.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Drug Monitoring; Evidence-Based Medicine; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes

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

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Drug Approval; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thrombosis; Warfarin

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

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

Non-vitamin K oral anticoagulants (NOACs) do not require routine laboratory monitoring. However, laboratory measurement may be desirable in special situations and populations.. This study's objective was to systematically review and summarize current evidence regarding laboratory measurement of the anticoagulant activity of dabigatran, rivaroxaban, and apixaban.. We searched PubMed and Web of Science for studies that reported a relationship between drug levels of dabigatran, rivaroxaban, and apixaban and coagulation assay results. Study quality was evaluated using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2).. We identified 17 eligible studies for dabigatran, 15 for rivaroxaban, and 4 for apixaban. For dabigatran, a normal thrombin time excludes clinically relevant drug concentrations. The activated partial thromboplastin time (APTT) and prothrombin time (PT) are less sensitive and may be normal at trough drug levels. The dilute thrombin time (R(2) = 0.92 to 0.99) and ecarin-based assays (R(2) = 0.92 to 1.00) show excellent linearity across on-therapy drug concentrations and may be used for drug quantification. For rivaroxaban and apixaban, anti-Xa activity is linear (R(2) = 0.89 to 1.00) over a wide range of drug levels and may be used for drug quantification. Undetectable anti-Xa activity likely excludes clinically relevant drug concentrations. The PT is less sensitive (especially for apixaban); a normal PT may not exclude clinically relevant levels. The APTT demonstrates insufficient sensitivity and linearity for quantification.. Dabigatran, rivaroxaban, and apixaban exhibit variable effects on coagulation assays. Understanding these effects facilitates interpretation of test results in NOAC-treated patients. More information on the relationship between drug levels and clinical outcomes is needed.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Benzimidazoles; beta-Alanine; Dabigatran; Drug Monitoring; Factor Xa Inhibitors; Humans; Morpholines; Partial Thromboplastin Time; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes

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

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

Although warfarin has historically been the dominant oral anticoagulant, newer target-specific oral anticoagulants (TSOACs) have been introduced in the marketplace in the past few years. Dabigatran, rivaroxaban, and apixaban, collectively referred to as TSOACs, have undergone extensive testing in comparison with warfarin and other anticoagulants for a variety of conditions. Compared with warfarin, the shorter time to peak effect, shorter half-life, and fewer drug-drug interactions have helped make the TSOACs attractive alternatives to warfarin for the prevention and treatment of thromboembolic disease associated with orthopedic surgery and atrial fibrillation as well as for the treatment of venous thromboembolism. However, their unique properties pose a challenge for their management in the perioperative period. This article reviews the current guideline-based approach to perioperative management of anticoagulants, the clinical data, and the recommendations supporting use of the TSOACs in the perioperative period. The article also addresses common pitfalls in their perioperative management. By understanding a few key properties of the new oral anticoagulants and with careful perioperative planning, physicians can ensure that their patients will safely undergo most surgical procedures with minimal disruption of their chronic anticoagulation.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Drug Monitoring; Humans; Kidney Function Tests; Morpholines; Perioperative Period; Practice Guidelines as Topic; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thromboembolism; Warfarin

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

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

The target-specific oral anticoagulants have recently been introduced as alternatives to warfarin for both prophylactic and therapeutic indications. Although their efficacy and side-effect profiles have been favorable, there is significant concern about management of hemorrhage with these agents as there is no direct reversal agent available. It is important for clinicians to be aware of these agents and the issues that surround them. Most of the management of hemorrhage is based on expert opinion and case reviews. Given the potentially catastrophic consequences of acute hemorrhage while patients are on anticoagulation, specific treatments are needed. Some methods that have been described include activated charcoal, hemodialysis, prohemostatic agents, and transfusions. Target-specific therapies have been shown to be effective in early studies in animal models; however, the effects in humans are still under investigation. More investigation is needed on the management of bleeding complications from target-specific oral anticoagulants.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Blood Transfusion; Charcoal; Dabigatran; Drug Monitoring; Factor Xa Inhibitors; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridones; Renal Dialysis; Rivaroxaban; Thiophenes

Stroke is becoming a major cause of morbidity and mortality in the developing world while the trend is actually downward in the developed nations. This is mostly because of the better recognition, treatment options and secondary prevention in addition to changes in lifestyles. There have been significant developments in the secondary prevention of ischaemic stroke in the last decade alone. Newer medications like direct thrombin inhibitors and factor Xa inhibitors have come into common practice. These medications are either equally effective or even better than age-old warfarin. Unlike previous belief, we now know that mechanical closure of the patent foramen ovale does not reduce the rate of stroke recurrence. There is a hint that dual anti-platelet therapy may reduce early recurrence of stroke. Even more exciting news is that closure of left atrial appendage might totally eliminate the need for oral anticoagulation in selected patient population.

Topics: Anticoagulants; Blood Coagulation; Brain Ischemia; Foramen Ovale, Patent; Humans; Intracranial Embolism; Morpholines; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Rivaroxaban; Secondary Prevention; Stroke; Thiophenes; Ventricular Dysfunction, Left

Venous thromboembolism (VTE) is a major cause of morbidity, mortality, and healthcare expenditure. In the United States, approximately 0.1 % of the population experiences an initial VTE event each year. Anticoagulation therapy is the cornerstone of acute VTE treatment and for prevention of recurrent VTE events. Conventional anticoagulants, including heparin, low-molecular-weight heparins, fondaparinux, and vitamin K antagonists are widely used but have limitations. Newer oral anticoagulant agents, including direct thrombin inhibitors (e.g., dabigatran etexilate) and direct factor Xa inhibitors (e.g., rivaroxaban, apixaban, and edoxaban) have been developed to attempt to overcome some of the limitations of conventional anticoagulant therapy. These new oral agents have been evaluated for safety and efficacy in large, randomized clinical trials in the treatment and secondary prevention of VTE with results that are comparable to conventional therapy. Dabigatran, rivaroxaban, apixaban, and edoxaban are important new treatment options for patients with VTE. In this review, we compare these new agents and their associated clinical trials in VTE treatment.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Venous Thromboembolism

Non-valvular atrial fibrillation is one of the most important risk factor for embolic cerebral infarcts. Besides vitamin K antagonists, recently developed novel oral anticoagulants are gaining an increasing role in its treatment. Dabigatran, rivaroxaban and apixaban are novel oral anticoagulants available in the routine clinical practice. This review summarizes their use and the corresponding guidelines in the secondary prevention of ischemic stroke, by answering questions raised in relation of a hypothetical case report.. A nem valvularis eredetű pitvarfibrilláció az embóliás agyi infarktusok egyik legfontosabb kockázati tényezője. Kezelésében a K-vitamin-antagonisták mellett az elmúlt években megjelenő új típusú orális antikoagulánsok egyre nagyobb teret kapnak. A dabigatran, a rivaroxaban és az apixaban a klinikai gyakorlatban elérhető új típusú orális antikoagulánsok. Az összefoglaló ezek alkalmazásának irányelveit, tulajdonságaikat tekinti át ischaemiás stroke szekunder prevenciójában, hipotetikus esetismertetés kapcsán felmerülő kérdéseket tárgyalva. Orv. Hetil., 2014, 155(42), 1655–1660.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Drug Administration Schedule; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Secondary Prevention; Stroke; Thiophenes; Vitamin K; Warfarin

EDUCATIONAL OBJECTIVES As a result of reading this article, physicians should be able to: 1. Recognize the high risk of postoperative venous thromboembolism (VTE) in patients undergoing major orthopedic surgery. 2. Distinguish the different pharmacological mechanisms of VTE prophylaxis drugs. 3. Delineate the advantages and disadvantages of each VTE prophylaxis drug. 4. Recognize that rivaroxaban is as efficacious as apixaban but can increase the risk of hemorrhage. Patients undergoing major orthopedic surgery are at high risk for developing postoperative venous thromboembolism (VTE). The authors analyzed the available evidence on the efficacy and safety of dabigatran, apixaban, and rivaroxaban vs low-molecular-weight heparins (LMWHs) as VTE prophylaxis in major orthopedic surgery. Outcomes evaluated included total VTE, deep venous thrombosis (DVT), pulmonary embolism (PE), death, and major bleeding. Rivaroxaban and apixaban are more efficacious than dabigatran and are as safe as dabigatran. Rivaroxaban is as efficacious as apixaban but can increase the risk of hemorrhage.

Topics: Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Heparin, Low-Molecular-Weight; Humans; Morpholines; Orthopedic Procedures; Postoperative Complications; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism

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

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Blood Coagulation Tests; Dabigatran; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Thiophenes; Vitamin K

To compare key features of the new oral anticoagulants (NOACs)-dabigatran, rivaroxaban, and apixaban-and to address questions that arise when comparing the NOACs.. PubMed was searched for recent (January 2008 to week 32 of 2013) clinical studies relating to NOAC use for stroke prevention in atrial fibrillation (AF) and for the treatment of acute venous thromboembolism (VTE).. All NOACs are at least as effective as warfarin for stroke prevention in patients with nonvalvular AF, and are at least as safe in terms of bleeding risk according to 3 large trials. Meta-analyses of these trials have shown that, compared with warfarin therapy, NOACs reduced total mortality, cardiovascular mortality, and intracranial bleeding, and there was a trend toward less overall bleeding. Practical advantages of NOACs over warfarin include fixed once- or twice-daily oral dosing without the need for coagulation monitoring, and few known or defined drug or food interactions. Potential drawbacks of NOACs include a risk of bleeding that might be increased in patients older than 75 years, increased major gastrointestinal bleeding with high-dose dabigatran, increased dyspepsia with dabigatran, the lack of a routine laboratory test to reliably measure anticoagulant effect, and the lack of an antidote for reversal. No direct comparisons of NOACs have been made in randomized controlled trials, and the choice of NOAC is influenced by individual patient characteristics, including risk of stroke or VTE, risk of bleeding, and comorbidity (eg, renal dysfunction).. The NOACs represent important alternatives in the management of patients with AF and VTE, especially for patients who have difficulty accessing regular coagulation monitoring. The companion to this article addresses common "what if" questions that arise in the long-term clinical follow-up and management of patients receiving NOACs.

Topics: Acute Disease; Administration, Oral; Anticoagulants; Antidotes; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Drug Monitoring; Family Practice; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Venous Thromboembolism; Warfarin

Despite an early invasive strategy and the use of dual antiplatelet therapy, patients with acute coronary syndrome (ACS) continue to be at substantial risk for recurrent ischemic events. It is believed that this risk is, at least in part, due to an intrinsic coagulation pathway that remains activated for a prolonged period after ACS. Earlier studies using warfarin showed a reduction in ischemic events, but the overall benefits were offset by increased bleeding complications. Recently, there has been increased interest in the potential role of new oral anticoagulants, some of which target factor Xa, after ACS. Factor Xa is important for the coagulation pathway and also plays a role in cellular proliferation and inflammation. It may thus be an attractive target for therapeutic intervention in ACS. Recently, various oral factor Xa inhibitors have been studied as potential treatment options for ACS. This review will focus on currently available data to evaluate the possible role of factor Xa inhibitors in the management of patients with ACS.

Topics: Acute Coronary Syndrome; Administration, Oral; Azepines; Benzamides; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Treatment Outcome

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

The use of new oral anticoagulants (NOACs) is expected to rise significantly in upcoming years. Therefore, it is important to understand the potential uses, side effects, and management of these agents in routine practice. NOACs have major pharmacologic advantages over warfarin, including a rapid onset and offset of action, fewer drug interactions, and predictable pharmacokinetics. These agents are gaining popularity among both physicians and patients because of their ease of administration and the advantage of eliminating the requirement for regular coagulation monitoring. NOACs work to prevent and treat thrombosis by targeting either thrombin (as with dabigatran) or factor Xa (as with rivaroxaban and apixaban). In this review, we discuss practical recommendations for the use of NOACs and the risks and benefits of incorporating them into routine practice.

Topics: Administration, Oral; Anticoagulants; Blood Coagulation; Dabigatran; Drug Interactions; Humans; Pyrazoles; Pyridones; Rivaroxaban; Thrombosis

Secondary prevention of atherothrombotic events is the domain of antiplatelet therapy and according to present risk is used one drug strategy or combination of acetylsalicylic acid with ADP receptor blockers. The importance of the combination of dual antiplatelet therapy together with xabans or dabigatran was investigated in 6 clinical trials. Only one of them (ATLAS ACS 2-TIMI 51) indicated that treatment with small dose of rivaroxaban (2 × 2.5 mg) may be added to dual strategy of acetylsalicylic acid and clopidogrel. The risk of major bleeding event is increased and net clinical benefit is only about 0.5 % per year. Dual therapy with aspirin and prasugrel or tikagrelor is beneficial. In the second part of the review is discussed higher incidence of myocardial infarction in controlled group in the trial comparing treatment of dabigatran with warfarin. This relationship has not been resolved, however, in patients with higher risk of coronary events and indication of anticoagulant treatment with direct oral anticoagulants it is recommended to choose from xabans (apixaban and rivaroxaban).

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Aspirin; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Clopidogrel; Dabigatran; Hemorrhage; Humans; Morpholines; Myocardial Infarction; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyrazoles; Pyridones; Rivaroxaban; Secondary Prevention; Thiophenes; Ticlopidine; Warfarin

Managing patients in the perioperative setting receiving novel oral anticoagulation agents for thromboprophylaxis or stroke prevention with atrial fibrillation is an important consideration for clinicians. The novel oral anticoagulation agents include direct Factor Xa inhibitors rivaroxaban and apixaban, and the direct thrombin inhibitor dabigatran. In elective surgery, discontinuing their use is important, but renal function must also be considered because elimination is highly dependent on renal elimination. If bleeding occurs in patients who have received these agents, common principles of bleeding management as with any anticoagulant (including the known principles for warfarin) should be considered. This review summarizes the available data regarding the management of bleeding with novel oral anticoagulation agents. Hemodialysis is a therapeutic option for dabigatran-related bleeding, while in vitro studies showed that prothrombin complex concentrates are reported to be useful for rivaroxaban-related bleeding. Additional clinical studies are needed to determine the best method for reversal of the novel oral anticoagulation agents when bleeding occurs.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Critical Care; Dabigatran; Hemorrhage; Humans; Intensive Care Units; Morpholines; Perioperative Care; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Warfarin

Novel oral anticoagulants (OACs), including dabigatran etexilate, rivaroxaban, and apixaban, are available alternative anticoagulant therapy to vitamin K antagonists. The US Food and Drug Administration (FDA) has approved dabigatran, rivaroxaban, and apixaban for the treatment of appropriate patients for specific clinical indications. Therapeutic advantages of prescribing the new OACs are related to their predictable pharmacokinetic and pharmacodynamic properties. Dabigatran, rivaroxaban, and apixaban have all been shown to be noninferior to warfarin treatment for stroke prevention in respective phase 3 clinical trials; dabigatran and apixaban were shown to be superior to warfarin as preventive therapy. Dabigatran, rivaroxaban, and apixaban are all approved agents for stroke prevention in patients with nonvalvular atrial fibrillation in the United States and Europe. Among these agents, rivaroxaban is the only FDA-approved drug for the treatment of venous thromboembolism. This article reviews the major clinical trials that investigated the efficacy and safety of the new OACs and the use of these agents in special clinical situations.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; Clinical Trials as Topic; Dabigatran; Drug Approval; Europe; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Therapeutic Equivalency; Thiophenes; United States; United States Food and Drug Administration; Venous Thromboembolism; Warfarin

Patients with atrial fibrillation (AF) face an elevated risk of stroke compared with patients who have normal sinus rhythm. Warfarin, an oral vitamin K antagonist, is a highly effective therapeutic agent to reduce stroke risk in patients with AF; however, use of warfarin is complicated by variable patient dose response due to genetic factors and multiple food-drug and drug-drug interactions. Novel oral anticoagulants appear to be a safe, effective alternative to warfarin therapy without the need for routine coagulation monitoring. Dabigatran, a direct thrombin inhibitor, has been commercially available since 2010 for prevention of stroke in patients with nonvalvular AF. More recently, the US Food and Drug Administration (FDA) approved 2 oral activated factor X inhibitors, rivaroxaban and apixaban, for stroke prevention in patients with AF based on clinical trial evidence of their safety and efficacy. In this article, we provide an overview of the 3 novel oral anticoagulants for treating patients with AF and discuss the latest findings from subgroup analyses.

Topics: Administration, Oral; Aging; Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Comorbidity; Dabigatran; Hemorrhage; Humans; Meta-Analysis as Topic; Morpholines; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Stroke; Thiophenes; Warfarin

For > 50 years, vitamin K antagonists were the only available oral drugs for the prevention of thromboembolism in patients with atrial fibrillation. Recently, new oral anticoagulants (the direct thrombin inhibitor dabigatran and the direct activated factor X (factor Xa) inhibitors rivaroxaban and apixaban) have completed phase 3 clinical trials for the same indications. The direct factor Xa inhibitor apixaban was approved by the US Food and Drug Administration in December 2012. In this article, we provide a comprehensive assessment of the safety and efficacy of the new oral anticoagulants. We focus primarily on the balance between thromboembolic and hemorrhagic risk and the implications of such risks in clinical practice. Bleeding and thromboembolic risk estimation tools and their roles in the correct utilization of new oral anticoagulation are also discussed.

Topics: Administration, Oral; Adult; Age Distribution; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Hemorrhage; Humans; Middle Aged; Morpholines; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Stroke; Thiophenes; Thromboembolism; Warfarin

Two different regimens of enoxaparin (40 mg once daily or 30 mg bid) have been used as control arms in trials of new oral anticoagulants. The choice of enoxaparin comparator may influence the perceived relative efficacy and safety of the newer agents, and we aimed to identify any significant differences between the two enoxaparin regimens.. We searched MEDLINE, EMBASE, and Cochrane Library for randomized controlled trials that compared enoxaparin to oral anticoagulant (apixaban, dabigatran, rivaroxaban) thromboprophylaxis in elective total knee or hip arthroplasty. Total VTE and bleeding events were pooled using fixed-effects meta-analysis and heterogeneity assessed with the I2 statistic. We conducted adjusted indirect comparisons of bid vs once-daily enoxaparin regimes based on new oral anticoagulants as common comparators.. Fourteen randomized controlled trials in hip and knee replacement surgery met the inclusion criteria. Adjusted indirect comparison showed that bid enoxaparin was significantly more effective in preventing VTE than enoxaparin once daily (relative risk [RR], 0.71; 95% CI, 0.61-0.83; P < .00001). For major and clinically relevant hemorrhage, adjusted indirect comparison showed that enoxaparin bid was nonsignificantly associated with increased risk of bleeding (RR 1.27; 95% CI, 0.97-1.65; P = .08) above that of enoxaparin once daily. Subgroup analysis limited to total knee arthroplasty trials showed similar results.. The use of once-daily enoxaparin regimen as control in clinical trials will lead to more favorable estimates of relative efficacy for the new oral anticoagulants than if enoxaparin 30 mg bid had been chosen as a comparator.

Topics: Administration, Oral; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Benzimidazoles; beta-Alanine; Dabigatran; Enoxaparin; Humans; Morpholines; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiophenes; Venous Thromboembolism

Apixaban and rivaroxaban are oral direct factor Xa (FXa) inhibitors used for VTE prevention after total hip (THA) and total knee arthroplasty (TKA). A meta-analysis of level I studies comparing rivaroxaban 10 mg daily or apixaban 2.5 mg twice daily to enoxaparin for the prevention of VTE after THA or TKA was performed analyzing efficacy and safety outcomes. Seven studies met the inclusion criteria including 24,385 patients. Oral FXa inhibitors were superior to enoxaparin in preventing DVT (p<0.00001). There was no difference in the rate of PE, death, major bleeding, blood transfusion requirement, reoperation for bleeding or postoperative wound infections. Oral FXa inhibitors are superior to enoxaparin in preventing DVT after THA and TKA. There is no difference in the rate of PE, death, or postoperative wound complications.

Topics: Administration, Oral; Anticoagulants; Arthroplasty, Replacement; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thrombosis

Thromboembolic diseases are common. Heparins and the vitamin K antagonists have been the mainstay of therapy for > 60 years, but both classes of agents have limitations. The "ideal" anticoagulant should be as effective and safe as heparin and vitamin K antagonists but should also be available in both a parenteral and an oral formulation, have predictable pharmacokinetics, and lack significant toxicities unrelated to the anticoagulant activity. Moreover, it should target a specific coagulation factor and have an antidote that leads to rapid reversal. There are now agents that fulfill some of these criteria. Here we review the pharmacology and effectiveness of the oral activated factor X inhibitors rivaroxaban and apixaban and the oral direct thrombin inhibitor dabigatran. These agents have undergone extensive phase 3 testing and are currently approved for various indications in the United States, Canada, or Europe. Rivaroxaban is approved in the United States for VTE prevention after major orthopedic surgery and for stroke prevention in atrial fibrillation and is approved in Europe and Canada for secondary prevention of VTE. Apixaban is currently under review by the US Food and Drug Administration for stroke prevention and is approved in Europe for VTE prevention following major orthopedic surgery. Dabigatran is approved in the United States for stroke prevention in nonvalvular atrial fibrillation and is being reviewed for secondary prevention of VTE.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Factor Xa Inhibitors; Humans; Morpholines; Pulmonary Embolism; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thrombin

The introduction of several oral direct anticoagulants within the past 2-3 years has dramatically changed clinical practice and has also impacted on utilization and interpretation of coagulation laboratory testing. This article reviews the effects of the oral thrombin inhibitor, dabigatran, and the oral factor Xa inhibitors, rivaroxaban and apixaban, on screening and diagnostic coagulation tests, and describes methods for measuring the their anticoagulant activity in plasma. Currently, there are evidence gaps regarding the role of laboratory testing for surveillance and management of adverse events associated with these new anticoagulants which do not require routine therapeutic drug monitoring. This is a rapidly changing field, and coagulation laboratory experts have a major role in ensuring patients receive appropriate testing and accurate interpretations of results.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Blood Coagulation; Blood Coagulation Tests; Dabigatran; Humans; Morpholines; Outcome Assessment, Health Care; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thrombosis

The objective of this review was to compare the safety and efficacy of dabigatran, rivaroxaban and apixaban to warfarin for the management of atrial fibrillation (AF) in older adults. The prevalence and incidence of AF increase with age. Approximately 5 % of the United States population over the age of sixty-five years and 10 % over the age of seventy-nine years have AF. AF is associated with increased risk for thromboembolic events. Despite the increasing incidence and prevalence of AF in older adults and the risks of thromboembolic events, clinicians often avoid anticoagulants. Specifically with warfarin, the risk of hemorrhage may outweigh the benefit in stroke risk reduction in certain populations. Aspirin, while safer to use, is not as effective as warfarin in stroke risk reduction. Newer non-vitamin K dependent antithrombotic therapies (e.g. dabigatran, rivaroxaban, and apixaban) are redefining thromboprophylaxis of AF. Dabigatran, rivaroxaban, and apixaban are at least as effective as warfarin in stroke risk reduction. With new mechanisms of action and no need for therapeutic drug monitoring, countless new patients are potential candidates for anticoagulation. However patient adherence, lack of a reversal agent, cost, and other safety concerns remain reasons for caution and careful consideration. Furthermore, older adults exhibited greater adverse effects from these agents across the clinical trials. This review will examine the newer anticoagulants safety and efficacy with particular attention to their role in treating older adults with AF. Alternatives to warfarin therapy now exist for thromboprophylaxis of AF. Whether these agents represent advances in overall safety in older adults remains uncertain. More experience and research are needed before endorsing their widespread use as a replacement for warfarin in the geriatric population.

Topics: Aged; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Drug Interactions; Fibrinolytic Agents; Humans; Morpholines; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Thiophenes; Warfarin

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

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

Novel oral anticoagulants are approved in several indications: rivaroxaban, apixaban, and dabigatran for the prevention of venous thromboembolism after elective hip or knee replacement surgery, and edoxaban for hip or knee replacement surgery and hip fracture surgery (in Japan only); rivaroxaban for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE; and rivaroxaban, apixaban, and dabigatran for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. These agents overcome some limitations of traditional anticoagulants, are suggested to have no requirement for routine coagulation monitoring, and are administered orally. Rivaroxaban, apixaban, and dabigatran have different pharmacological characteristics, and guidance is needed on optimum doses and dosing intervals and the effects of renal or hepatic impairment, age, food, and other drugs. Dabigatran has stricter prescribing advice than rivaroxaban or apixaban for patients with moderate-to-severe renal impairment. All three drugs have restrictions on use in patients with hepatic impairment. Apixaban requires twice-daily dosing in all indications, whereas rivaroxaban and dabigatran are dosed once- or twice-daily depending on indication. Although head-to-head comparisons are lacking, the novel oral anticoagulants may show favorable cost-benefit relations compared with traditional vitamin K antagonists or no therapy.. This review summarizes the pharmacology of rivaroxaban, apixaban, edoxaban, and dabigatran, and the indications for which they are approved. Issues regarding the optimization of the use of these anticoagulants for the management of thromboembolic disorders will also be discussed.

Topics: Administration, Oral; Animals; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes

Anticoagulant prophylaxis with vitamin K antagonists (such as warfarin) is effective in reducing the risk of stroke in patients with atrial fibrillation (AF). New oral anticoagulants have emerged as potential alternatives to traditional oral agents. The purpose of this review was to summarise the effectiveness and safety of rivaroxaban, dabigatran and apixaban in stroke prevention in patients with AF in phase III trials, evaluate their cost-effectiveness and consider the implications for primary care.. A literature search was performed between 2007 and 2012, selecting all phase III trials (ROCKET AF, RE-LY and ARISTOTLE) of new oral anticoagulants and relevant cost-benefit studies.. Evidence shows that all three agents are at least as effective as warfarin in the prevention of stroke and systemic emboli, with similar safety profiles. Cost-benefit studies of rivaroxaban and dabigatran further confirm their potential use as alternatives to warfarin in clinical practice. These observations may allow stratification of the general practice AF population, to help prioritise which patients may benefit from receiving a new oral anticoagulant.. The clinical and economic benefits of the new oral anticoagulants, along with appropriate risk stratification, may enable a higher number of patients with AF to receive effective and convenient prophylaxis for stroke prevention.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Clinical Trials, Phase III as Topic; Cost-Benefit Analysis; Dabigatran; Female; Hemorrhage; Humans; Male; Morpholines; Primary Health Care; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Treatment Outcome; Workload

Vitamin K antagonists were the only class of oral anticoagulants available to clinicians for decades. However, with the US Food and Drug Administration approval of new oral anticoagulants, such as dabigatran, rivaroxaban, and apixaban, clinicians now have a broader choice. Given the recent approval and availability of these medications, several questions arise while deciding which of them would be best suited for a particular patient. This article provides a concise review for clinicians entailing the main studies that evaluated the efficacy and safety of these drugs, their pharmacokinetic and pharmacodynamic properties, and a practical approach to their clinical use. For this review, we conducted searches of PubMed and MEDLINE for articles published between January 1, 2000, and January 30, 2013, using the following search terms: oral anticoagulants, dabigatran, apixaban, rivaroxaban, novel anticoagulants, bleeding complications, management of bleeding complications, pharmacodynamics, and pharmacokinetics. Studies published in English were selected for inclusion in this review, as were additional articles identified from bibliographies.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Treatment Outcome

The current mainstay of treatment of thrombotic APS is long-term anticoagulation with oral vitamin K antagonists (VKA) such as warfarin. However, the use of warfarin is problematic, particularly in patients with antiphospholipid syndrome (APS). The new oral anticoagulants (NOAC) include dabigatran etexilate (Pradaxa®), a direct thrombin inhibitor, and rivaroxaban (Xarelto®), Apixaban (Eliquis) and Edoxaban (Lixiana®), which are direct anti-Xa inhibitors. Unlike warfarin, these agents do not interact with dietary constituents and alcohol, have few reported drug interactions, and monitoring of their anticoagulant intensity is not routinely required due to their predictable anticoagulant effects. In this chapter, we discuss clinical and laboratory aspects of NOAC. These agents have been approved for several therapeutic indications based on phase III prospective randomised controlled clinical trials using warfarin at a target INR of 2.5 (i.e. range 2.0-3.0) as the comparator. However these trials may not be directly applicable to patients with antiphospholipid syndrome (APS) where prospective clinical studies of NOAC are the way forward.

Topics: Administration, Oral; Adult; Animals; Anticoagulants; Antiphospholipid Syndrome; Benzimidazoles; beta-Alanine; Breast Feeding; Clinical Trials, Phase III as Topic; Contraindications; Dabigatran; Drug Monitoring; Female; Humans; Infant, Newborn; Maternal Exposure; Morpholines; Pregnancy; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiazoles; Thiophenes

Chronic kidney disease and atrial fibrillation (AF) commonly coexist, and data suggest that renal patients have AF rates in excess of double that encountered in the general population. These patients are at increased risk of stroke, regardless of the presence or absence of AF. Furthermore, a lower GFR causes increased thromboembolic risk in patients with AF - independent of other risk factors. The dilemma facing clinicians treating this cohort of patients is that renal insufficiency confers both a thromboembolic and a bleeding risk. Renal disease also commonly coexists with other risk factors for stroke and bleeding such as hypertension and advanced age. Furthermore, bleeding risk tracks stroke risk and many risk factors are common to both thromboembolism and haemorrhage. Patients with severe renal impairment are also actively excluded from the majority of trials for stroke prevention in AF, including those trials which informed the development of stroke risk factor scoring schemes. Therefore, patients with renal disease and AF present a unique management challenge. The available data suggests that the benefit from warfarin in terms of stroke reduction is not as clear as in the general population, and there is an increased risk of bleeding complications and even ectopic vascular calcification. Thus, it is problematic to extrapolate the benefits of warfarin in the general population to a subgroup that has been actively excluded from clinical trials. The new oral anticoagulants have relatively little data in patients with severe renal impairment, and all have an element of renal excretion. There is a need for large randomised control trials in patients with renal insufficiency and on haemodialysis to provide a bank of high-quality scientific data on which clinicians can base their management decisions. Until then, we must adopt a pragmatic approach which involves careful consideration of the relative risk of stroke and bleeding in each individual patient.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Comorbidity; Dabigatran; Disease Management; Embolism; Female; Fibrinolytic Agents; Hemorrhage; Humans; Hypertension; Intracranial Embolism; Male; Morpholines; Patient Selection; Pyrazoles; Pyridones; Renal Insufficiency, Chronic; Risk; Risk Factors; Rivaroxaban; Severity of Illness Index; Stroke; Thiophenes; Thrombophilia; Warfarin

To review novel oral anticoagulant (NOAC) trials in the treatment of venous thromboembolism (VTE) and the possible use of risk-stratification tools to guide their use in practice.. MEDLINE and Cochrane databases were searched to identify relevant journal articles published from January 1982 to February 2013. Additional references were obtained from articles extracted during the database search.. NOACs have been developed to optimize VTE management and overcome the limitations of heparin and vitamin K antagonists (VKA). The AMPLIFY and EINSTEIN trials of apixaban and rivaroxaban, respectively, investigated single-drug management of VTE, whereas the edoxaban Hokusai-VTE trial and dabigatran RE-COVER and RE-COVER II trials investigated the use of NOACs with a heparin lead-in. The AMPLIFY and Hokusai-VTE trials are ongoing but the EINSTEIN and RE-COVER trials have demonstrated that rivaroxaban and dabigatran, respectively, are non-inferior to parenteral anticoagulants and warfarin in the management of VTE. Differences in study design complicate the application of study results to clinical practice. There are multiple validated DVT protocols that effectively and safely treat patients in outpatient settings. The pulmonary embolism (PE) severity index (PESI), simplified PESI (sPESI), and other prognostic tools have been used to risk stratify patients with PE by estimating mortality risk to guide outpatient eligibility.. NOACs provide physicians with new therapeutic options in the management of VTE. While heparin and VKAs compose the current standard treatment for VTE, their use will likely disappear as physicians grow comfortable with the adoption of NOACs. As studies have not clearly defined the efficacy of these agents in certain patient populations, further data in special patient populations and risk stratification through the use of VTE severity scores could potentially be adapted to guide anticoagulant management and outpatient treatment eligibility.

Topics: Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Factor X; Heparin; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Thrombin; Venous Thromboembolism; Vitamin K; Warfarin

Dabigatran, apixaban, and rivaroxaban have been approved for primary and secondary stroke prevention in patients with atrial fibrillation. However, questions have arisen about how to manage emergency situations, such as when thrombolysis would be required for acute ischemic stroke or for the managing intracranial or gastrointestinal bleedings. We summarize the current literature and provide recommendations for the management of these situations. Peak plasma levels of the direct oral anticoagulants (DOACs) apixaban, dabigatran, or rivaroxaban are observed about 2-4 h after intake. Elimination of dabigatran is mainly dependent on renal function. Consequently, if renal function is impaired, there is a risk of drug accumulation that is highest for dabigatran followed by rivaroxaban and then apixaban and thus dosing recommendations are different. To date, no bedside tests are available that reliably assess the anticoagulatory effect of DOACs, nor are specific antidotes available. We recommend performing the following tests if DOAC intake is unknown: dabigatran-associated bleeding risk is minimized or can be neglected if thrombin time, Hemoclot test, or Ecarin clotting time is normal. Apixaban and rivaroxaban effects can be ruled out if findings from the anti-factor Xa activity test are normal. High plasma levels of DOAC are also mostly excluded if PTT and PTZ are normal four or more hours after DOAC intake. However, normal values of global coagulation tests are not sufficient if thrombolysis is indicated for treating acute stroke. The decision for or against thrombolysis is an individual decision; in these cases, thrombolysis use is off-label. In case of bleeding, prothrombin complex concentrates seems to be the most plausible treatment. For severe gastrointestinal bleeding with life-threatening blood loss, the bleeding source needs to be identified and treated by invasive measures. Use of procoagulant drugs (antifibrinolytics) might also be considered. However, there is very limited clinical experience with these products in conjunction with DOAC.

Topics: Administration, Oral; Animals; Anticoagulants; Antithrombins; Benzimidazoles; beta-Alanine; Dabigatran; Dose-Response Relationship, Drug; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridones; Renal Insufficiency; Rivaroxaban; Thiophenes

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

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Blood Coagulation Factors; Cerebral Hemorrhage; Dabigatran; Factor Xa Inhibitors; Humans; Monitoring, Physiologic; Morpholines; Prodrugs; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Thrombin; Thromboembolism; Vitamin K; Warfarin

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; Dabigatran; Gastrointestinal Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiophenes

Electrical cardioversions are performed to restore sinus rhythm in patients with non-valvular atrial fibrillation to improve symptoms. It has been known for decades that cardioversion without adequate anticoagulation for 3-4 weeks prior to and for 4 weeks after cardioversion results in thromboembolic complication of about 5%. It is much less known that cardioversion is also associated with a higher risk of thromboembolism (stroke, peripheral embolism) in patients treated with usual anticoagulation. The control arms (warfarin) of the three studies with the new anticoagulants dabigatran, rivaroxaban, and apixaban for the prevention of thromboembolism in non-valvular atrial fibrillation report a monthly thromboembolic risk of 0,13-0,2%. The risk for thromboembolic complication in the month following cardioversion is about three to six times higher than without cardioversion in patients with non-valvular atrial fibrillation treated with usual anticoagulation. Since most cardioversions are performed by DC shock it is not known whether electrical and pharmacological cardioversions carry the same risk for thromboembolism. Although thromboembolic complications do not often occur following cardioversion the increased risk due to this procedure should be acknowledged. Strict anticoagulation (e. g. INR value > 2,5) in the first 10-14 days following cardioversion could possibly minimize the risk of thromboembolism.

Topics: Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Drug Administration Schedule; Electric Countershock; Enoxaparin; Heparin; Humans; International Normalized Ratio; Morpholines; Phenprocoumon; Practice Guidelines as Topic; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Risk Factors; Rivaroxaban; Stroke; Thiophenes; Thromboembolism; Warfarin

Patients with atrial fibrillation are at an increased risk for stroke. Anticoagulation therapy has been shown to significantly reduce the risk for stroke in these patients. Warfarin therapy is effective at reducing the risk for thromboembolic events, but requires frequent monitoring of its anticoagulation effect using the international normalized ratio and significantly increases the risk for hemorrhagic events, including intracranial hemorrhage. Novel oral anticoagulants provide simpler, effective stroke prophylaxis in patients with atrial fibrillation. These drugs include dabigatran (a direct thrombin inhibitor) as well as rivaroxaban and apixaban (factor Xa inhibitors). The new anticoagulants have rapid onset of effect; their anticoagulatory effect is stable, predictable, and dose related; and they do not require monitoring of anticoagulation effect using the international normalized ratio. The pharmacology, clinical efficacy, and potential adverse effects of these drugs in patients with atrial fibrillation are reviewed herein.

Topics: Anticoagulants; Atrial Fibrillation; Benzimidazoles; Dabigatran; Humans; International Normalized Ratio; Morpholines; Pyrazoles; Pyridines; Pyridones; Risk Factors; Rivaroxaban; Stroke; Thiophenes

Warfarin has been the mainstay oral anticoagulant (OAC) medication prescribed for stroke prevention in atrial fibrillation (AF) patients. However, warfarin therapy is challenging because of marked interindividual variability in dose and response, requiring frequent monitoring and dose titration. These limitations have prompted the clinical development of new OACs (NOACs) that directly target the coagulation cascade with rapid onset/offset of action, lower risk for drug-drug interactions, and more predictable response. Recently, NOACs dabigatran (direct thrombin inhibitor), and rivaroxaban and apixaban (factor Xa [FXa] inhibitors) have gained regulatory approval as alternative therapies to warfarin. Though the anticoagulation efficacy of these NOACs has been characterized, differences in their pharmacokinetic and pharmacodynamic profiles have become a significant consideration in terms of drug selection and dosing. In this review, we outline key pharmacokinetic and pharmacodynamic features of each compound and provide guidance on selection and dosing of the 3 NOACs relative to warfarin when considering OAC therapy for AF patients. Importantly, we show that by better understanding the effect of clinical variables such as age, renal function, dosing interval, and drug metabolism (CYP3A4) and transport (P-glycoprotein), we might be able to better predict the risk for sub- and supratherapeutic anticoagulation response and individualize OAC selection and dosing.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Biological Availability; Blood Coagulation; Dabigatran; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Humans; Morpholines; Outcome Assessment, Health Care; Patient Selection; Polymorphism, Genetic; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Warfarin

The primary objective was to assess the cost-effectiveness of new oral anticoagulants compared with warfarin in patients with nonvalvular atrial fibrillation. Secondary objectives related to assessing the cost-effectiveness of new oral anticoagulants stratified by center-specific time in therapeutic range, age, and CHADS2 score.. Cost-effectiveness was assessed by the incremental cost per quality-adjusted life-year (QALY) gained. Analysis used a Markov cohort model that followed patients from initiation of pharmacotherapy to death. Transition probabilities were obtained from a concurrent network meta-analysis. Utility values and costs were obtained from published data. Numerous deterministic sensitivity analyses and probabilistic analysis were conducted.. The incremental cost per QALY gained for dabigatran 150 mg versus warfarin was $20,797. Apixaban produced equal QALYs at a higher cost. Dabigatran 110 mg and rivaroxaban were dominated by dabigatran 150 mg and apixaban. Results were sensitive to the drug costs of apixaban, the time horizon adopted, and the consequences from major and minor bleeds with dabigatran. Results varied by a center's average time in therapeutic range, a patient's CHADS2 score, and patient age, with either dabigatran 150 mg or apixaban being optimal.. Results were highly sensitive to patient characteristics. Rivaroxaban and dabigatran 110 mg were unlikely to be cost-effective. For different characteristics, apixaban or dabigatran 150 mg were optimal. Thus, the choice between these two options may come down to the price of apixaban and further evidence on the impact of major and minor bleeds with dabigatran.

Topics: Administration, Oral; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cardiovascular Diseases; Cost-Benefit Analysis; Dabigatran; Drug Costs; Hemorrhage; Humans; Markov Chains; Middle Aged; Morpholines; Pyrazoles; Pyridones; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Time Factors; Warfarin

New oral anticoagulants, including dabigatran, rivaroxaban, and apixaban, have been recently approved for primary and secondary prophylaxis of thromboembolic conditions. However, there is no clear strategy for managing and reversing their anticoagulant effects. We aimed to summarize the available evidence for clinical management and reversal of bleeding associated with new oral anticoagulants. Using a systematic review approach, we aimed to identify studies describing reversal strategies for dabigatran, rivaroxaban, and apixaban. The search was conducted using Medline, EMBASE, HealthSTAR, and grey literature. We included laboratory and human studies. We included 23 studies reported in 37 out of 106 potentially relevant references. Four studies were conducted in humans and the rest were in vitro and in vivo studies. The majority of the studies evaluated the use of prothrombinase complex concentrate (PCC), either activated or inactivated, and recombinant activated factor VII (rFVIIa). Other interventions were also identified. Laboratory studies suggest that hemostatic parameters and bleeding might be partially or completely corrected by PCC for rivaroxaban better than dabigatran. Studies in humans suggest that PCC might reverse the effects of rivaroxaban better than dabigatran assessed by hemostatic tests. We were not able to locate studies evaluating the clinical efficacy of these agents. The best available evidence suggests that PCC (activated or inactivated) might be the best option for reversing new anticoagulants. Evidence for rFVIIa is less compelling. There might be differences in the efficacy of reversing agents for different anticoagulants. Studies assessing the clinical efficacy of these reversal agents are urgently needed.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Disease Management; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes

The management of thromboprophylaxis in patients with pelvic and acetabular fractures remains a highly controversial topic within the trauma community. Despite anticoagulation, venous thromboembolism (VTE) remains the most common cause of surgical morbidity and mortality in this high-risk patient group. Although various thromboprophylactic regimes are employed, evidence relating to the most effective method remains unclear. Controversies surrounding screening, the use of prophylactic inferior vena cava filters (IVCF) and chemothromboprophylaxis in polytraumatised patients, particularly those with pelvic and acetabular fractures, form the basis of considerable debate. With the absence of a well-designed clinical trial and the presence of ongoing controversies within the literature, this review will explore current treatment options available to trauma surgeons and highlight differing scientific opinions, providing an update on the role of screening and current available preventative measures. We cover existing as well as recent advances in chemical thromboprophylactic agents and discuss external mechanical compression devices, the usefulness of serial duplex ultrasonography and the role of extended chemothromboprophylaxis on discharge. The evidence behind prophylactic IVCF is also considered, along with reported complication profiles. We conclude with a proposed protocol for use in major trauma centres, which can form the basis of local policy for the prevention of VTE in trauma patients with pelvic and acetabular fractures.

Topics: Acetabulum; Anticoagulants; Aspirin; Benzimidazoles; beta-Alanine; Coumarins; Dabigatran; Fondaparinux; Fractures, Bone; Heparin; Humans; Mass Screening; Morpholines; Multiple Trauma; Pelvis; Polysaccharides; Pulmonary Embolism; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Thiophenes; Vena Cava Filters; Venous Thromboembolism

Novel oral anticoagulants, direct thrombin inhibitors, and factor Xa inhibitors are being introduced into clinical practice. In contrast to vitamin K antagonists, such as warfarin, these novel agents, because of their relatively wide therapeutic range and predictable pharmacokinetics, have been evaluated in clinical trials and approved for clinical use without the need for routine coagulation monitoring. On occasion, it will be important to assess the anticoagulant status of patients treated with these agents. As a result of their targeted mechanisms of action, they affect standard coagulation assays differently than vitamin K antagonists and heparins, and such assay results may not provide clinically useful information. Thus, less commonly used coagulation assays (eg, chromogenic anti-factor Xa activity assays, diluted thrombin time, and ecarin-based clotting tests) may be introduced into clinical practice. These assays are currently limited by the absence of validated therapeutic targets and lack of standardization across laboratories, vendors, and medication classes. This article provides an overview of the coagulation assays and their potential role in determining the anticoagulant status of patients treated with the emerging anticoagulants.

Topics: Anticoagulants; Antithrombins; Benzimidazoles; beta-Alanine; Blood Coagulation Tests; Dabigatran; Drug Monitoring; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Thrombosis

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

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

The new oral anticoagulants dabigatran etexilate (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis) have predictable pharmacokinetic and pharmacodynamic profiles and are alternatives to warfarin. However, many physicians are wary of these drugs, since there is limited evidence on how to manage bleeding in patients taking them, and since no specific antidote is known to reverse their anticoagulant effect. Management requires careful adherence to first principles of bleeding care. Unapproved and untested reversal strategies may be required in patients with life-threatening bleeding.

Topics: Anticoagulants; Benzimidazoles; beta-Alanine; Blood Coagulation Tests; Dabigatran; Drug Monitoring; Hemorrhage; Hemostatic Techniques; Humans; Morpholines; Perioperative Care; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes

Warfarin has been the established oral anticoagulant for the last 50 years, being effective in the prevention and treatment of venous and arterial thromboembolic disorders. However, the frequent requirement for INR monitoring, multiple drug and food interactions have fuelled the need for development of new oral anticoagulants. Dabigatran is the first of a series of new oral anticoagulants that are emerging as the successors to warfarin. This new group of anticoagulants is rapidly gaining FDA and NICE approval and has proven non-inferiority to warfarin and viable alternatives to warfarin in the coming years. Given the obvious impact of this on dental treatment in the primary care and hospital setting this article aims to increase familiarisation with this new medicine group.

Topics: Anticoagulants; Antithrombin Proteins; Benzimidazoles; Dabigatran; Factor Xa Inhibitors; Humans; Morpholines; Prodrugs; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Thromboembolism; Warfarin

New direct oral anticoagulant agents (DOAC) are currently licensed for thromboprophylaxis after hip and knee arthroplasty and for long-term prevention of thromboembolic events in non-valvular atrial fibrillation as well as treatment and secondary prophylaxis of venous thromboembolism. Some other medical indications are emerging. Thus, anaesthesiologists are increasingly likely to encounter patients on these drugs who need elective or emergency surgery. Due to the lack of experience and data, the management of DOAC in the perioperative period is controversial. In this article, we review available information and recommendations regarding the periprocedural management of the currently most clinically developed DOAC, apixaban, dabigatran, and rivaroxaban. We discuss two trends of managing patients on DOAC for elective surgery. The first is stopping the DOAC 1-5 days before surgery (depending on the drug, patient and bleeding risk) without bridging. The second is stopping the DOAC 5 days preoperatively and bridging with low-molecular-weight heparin. The management of patients on DOAC needing emergency surgery is also reviewed. As no data exist for the use of haemostatic products for the reversal of the anticoagulant effect in these cases, rescue treatment recommendations are proposed.

Topics: Administration, Oral; Aged; Anesthesiology; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Benzimidazoles; beta-Alanine; Dabigatran; Female; Hemorrhage; Hemostasis; Heparin, Low-Molecular-Weight; Humans; Male; Morpholines; Patient Safety; Perioperative Period; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thromboembolism

Given the increasing prevalence of atrial fibrillation, the need for safe and effective stroke prophylaxis will continue to rise. Warfarin has been around for many years and has proven efficacy in preventing stroke, but it has major limitations due to its variable dosing, food and drug interactions, and requirement for regular monitoring. Newer agents which include dabigatran, rivaroxaban, and apixaban have recently or will soon be available and may provide an improved efficacy in stroke prevention, an improved safety profile, and improved user-friendliness. Dabigatran was the first of the agents to be widely available, and in the RE-LY study, dabigatran (150 mg dose) showed superiority to warfarin in preventing ischemic stroke and a significant reduction in intracranial bleeding. Rivaroxaban was studied in the ROCKETAF trial, and with once daily dosing, it showed noninferiority to warfarin in preventing stroke with a significant reduction in intracranial bleeding. The ARISTOTLE trial showed apixaban was superior to warfarin for stroke prevention, significantly reduced all major bleeding, and resulted in a significant reduction in all-cause mortality. While all three trials have important limitations, they were very large randomized trials with more than 14,000 patients each and show a clear overall net clinical benefit when compared with warfarin. Key features of the drugs as well as an individual's preferences and stability on warfarin will help guide the ultimate drug choice for any given patient, but these newer anticoagulant agents are likely to usher in a new era in stroke prevention in atrial fibrillation.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Humans; Morpholines; Prognosis; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Warfarin

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

Dabigatran, rivaroxaban and apixaban are oral anticoagulants used to prevent or treat thrombosis in a variety of situations. Like all anticoagulants, these drugs can provoke bleeding. How should patients be managed if bleeding occurs during dabigatran, rivaroxaban or apixaban therapy? How can the risk of bleeding be reduced in patients who require surgery or other invasive procedures? To answer these questions, we reviewed the available literature, using the standard Prescrire methodology. In clinical trials, warfarin, enoxaparin, dabigatran, rivaroxaban and apixaban were associated with a similar frequency of severe bleeding. Numerous reports of severe bleeding associated with dabigatran have been recorded since this drug was first marketed. Some situations are associated with a particularly high bleeding risk, including: even mild renal failure, advanced age, extremes in body weight and drug-drug interactions, particularly with antiplatelet agents (including aspirin), nonsteroidal antiinflammatory drugs, and many drugs used in cardiovascular indications. In patients treated with dabigatran, rivaroxaban or apixaban, changes in the INR (international normalised ratio) and activated partial thromboplastin time (aPTT) do not correlate with the dose. In early 2013, there is still no routine coagulation test suitable for monitoring these patients; specific tests are only available in specialised laboratories. In early 2013 there is no antidote for dabigatran, rivaroxaban or apixaban, nor any specific treatment with proven efficacy for severe bleeding linked to these drugs. Recommendations on the management of bleeding in this setting are based mainly on pharmacological parameters and on scarce experimen-Haemodialysis reduces the plasma concentration of dabigatran, while rivaroxaban and apixaban cannot be eliminated by dialysis. Prothrombin complex concentrates and recombinant activated factor VII seem to have little or no efficacy, and they carry a poorly documented risk of thrombosis. For patients undergoing surgery or other invasive procedures, clinical practice guidelines are primarily based on pharmacokinetic parameters and on extrapolation of data on vitamin K antagonists. The decision on whether or not to discontinue anticoagulation before the procedure mainly depends on the likely risk of bleeding. In patients at high risk of thrombosis, heparin can be proposed when the anticoagulant is withdrawn. In early 2013, difficulties in the management of bleedi

Topics: Anticoagulants; Antidotes; Benzimidazoles; beta-Alanine; Blood Coagulation Tests; Dabigatran; Drug Overdose; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes

Warfarin and aspirin are used to prevent stroke in patients with atrial fibrillation (AF). There are inherent challenges with both treatments, including variable and inconsistent benefit and increased bleeding risks. The availability of new anticoagulants offers some alternatives.. A mixed treatment comparison meta-analysis to evaluate direct and indirect treatment data including aspirin, warfarin apixaban, dabigatran, edoxaban, and rivaroxaban for the prevention of primary or secondary stroke in patients with AF.. A comprehensive, systematic literature search was conducted to identify randomized trials comparing aspirin, warfarin, apixaban, dabigatran, edoxaban, and rivaroxaban in patients with AF requiring treatment for stroke prevention. Open-label and blinded designs were included if they evaluated any stroke or any bleeding event. Data on stroke and bleeding events were abstracted, verified, evaluated, scored, and entered into Aggregate Data Drug Information System version 1.16 to generate a mixed treatment comparison meta-analysis. Direct and indirect comparisons were evaluated, and we looked for inconsistency in closed loop structures. Data are reported as rate ratios with 95% credible intervals. In addition, we reviewed variance statistics and explored variance with node-splitting models.. Our literature search yielded 30 articles, 21 of which were included. All treatments except aspirin reduced the risk of any stroke compared with placebo. Warfarin (0.43 [0.33-0.57]), apixaban (0.37 [0.27-0.54]), dabigatran (0.34 [0.21-0.57]), rivaroxaban (0.36 [0.22-0.60]), and aspirin with clopidogrel (0.73 [0.53-0.99]) were more protective than aspirin alone. Warfarin and the new anticoagulants were similar in the reduction of stroke, vascular death, and mortality. There was no difference in major bleeding between any treatment group. There were more nonmajor bleeding events when comparing warfarin and apixaban (1.83 [1.05-4.03]); no other differences between warfarin and the other new anticoagulants were found.. This mixed treatment comparison meta-analysis found similarity between warfarin and the new anticoagulants with the exception of one comparison, in which warfarin was associated with more non-major bleeding than apixaban. Thus, the new anticoagulants are therapeutically comparable when warfarin is inappropriate.

Topics: Anticoagulants; Aspirin; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Data Interpretation, Statistical; Databases, Bibliographic; Double-Blind Method; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Warfarin

New oral anticoagulants have been found to be as efficacious as warfarin and safer in terms of intracranial bleeding. All patients with nonvalvular atrial fibrillation should receive antithrombotic therapy for stroke prevention. For those at low risk, antiplatelet therapy is probably sufficient. For those at intermediate or high risk, anticoagulation is superior to antiplatelet therapy. Four oral anticoagulants are currently approved for stroke and systemic embolism prevention in atrial fibrillation: warfarin, dabigatran, rivaroxaban, and apixaban. Management of bleeding complications while on the new agents remains an area of concern and management is based on anecdotal experience and observational studies.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Humans; Male; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes

Until recently, warfarin had been one of the only treatment options for long-term anticoagulation of patients with atrial fibrillation, venous thromboembolism, or other medical conditions that require chronic anticoagulation. A main concern when treating patients with anticoagulants is balancing the benefits of preventing a thromboembolic event with the risks of bleeding events. The US Food and Drug Administration recently approved 2 new oral anticoagulants, dabigatran and rivaroxaban, for stroke prevention in patients with atrial fibrillation, and is currently reviewing a drug application for a third new oral anticoagulant, apixaban. These new anticoagulants do not require strict and frequent laboratory monitoring, dosing adjustments, or dietary restrictions, and they incur fewer drug-drug interactions than warfarin. However, these new medications do not have specific reversal agents, may require dosage adjustment based on patient renal function, and lack clinical data regarding their long-term safety and efficacy. The 2012 American College of Chest Physicians Evidence-Based Clinical Practice Guidelines for antithrombotic therapy and prevention of thrombosis include recommendations for dabigatran, rivaroxaban, and apixaban for certain indications. Each of the 3 novel oral anticoagulants has specific pharmacokinetic and pharmacodynamic properties that may make them suitable agents for use in specific patient populations. Knowledge of dosing, drug-drug interactions, monitoring parameters, and clinical considerations for each of these new medications will help clinicians decide for which patients they may be best suited to replace conventional therapy with warfarin.

Topics: Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Drug Administration Schedule; Humans; Morpholines; Postoperative Complications; Practice Guidelines as Topic; Pulmonary Embolism; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Venous Thromboembolism; Venous Thrombosis

Vitamin K antagonists have been in wide use for over 70 years. Warfarin, the most commonly used vitamin K antagonist, has been shown to be highly effective in treating and preventing thrombosis. Despite this, warfarin has many disadvantages, which has led to the development of a new class of oral anticoagulants targeted to specific coagulation factors designated as target-specific oral anticoagulants (TSOAs). TSOAs include the thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban, apixaban). This chapter reviews the disadvantages of warfarin and evaluates both the advantages and disadvantages of the new oral anticoagulants.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Drug Dosage Calculations; Drug Interactions; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiophenes; Thrombin; Thrombosis; Vitamin K; Warfarin

Atrial fibrillation (AF) confers a significant risk of stroke or systemic thromboembolism. Oral anticoagulation is the most effective therapy for AF-related stroke prevention. A decision to advise oral anticoagulation should be based upon the individual absolute risks of stroke and bleeding, and almost all AF patients with ≥1 stroke risk factors have a positive net clinical benefit of oral anticoagulation. The novel oral anticoagulants (NOACs) dabigatran, rivaroxaban and apixaban are more convenient, and are at least equally effective and safer (regarding bleeding complications) for stroke prevention compared with vitamin K antagonists (VKAs). Availability of NOACs and improved stroke and bleeding risks assessment should increase the number of AF patients who receive adequate thromboprophylaxis. In this review article, we present an overview of the clinical phase III trials with NOACs for stroke prevention and discuss the contemporary principles of thromboprophylaxis in AF patients with various stroke and bleeding risk profiles, as well as practical aspects of NOACs therapy.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Clinical Trials, Phase III as Topic; Dabigatran; Drug Administration Schedule; Humans; Intracranial Hemorrhages; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Thromboembolism

New oral anticoagulants (NOACs) have been developed that may further decrease the mortality and morbidity of ACS by complementing antiplatelet therapy. Optimal use of these agents can be achieved by maximum reduction in thrombotic events at the minimum bleeding risk when combining a long-term oral anticoagulant with anti-platelet therapy in patients with coronary heart disease. Although, based on the pharmacokinetics and -dynamics of NOACs, these agents could improve the current management of ACS patients, multiple trials consistently demonstrate a trend toward increased major and clinically relevant non major bleeding almost diminishing the benefits in reduction of ischemic events. Therefore, some critical issues need to be further evaluated in future trials.

Topics: Acute Coronary Syndrome; Administration, Oral; Aged; Anticoagulants; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Humans; Intracranial Hemorrhages; Morpholines; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thrombin; Thromboembolism

In patients with atrial fibrillation (AF) oral anticoagulation with vitamin-K antagonists (warfarin, phenprocoumon) is effective both for primary and secondary stroke prevention yielding a 60-70% relative reduction in stroke risk compared with placebo, as well as a mortality reduction of 26 percent. Vitamin-K antagonists have a number of well documented shortcomings. Recently the results of randomised trials for three new oral anticoagulants that do not exhibit the limitations of vitamin-K antagonists have been published. These include direct factor Xa inhibitors (rivaroxaban and apixaban) and a direct thrombin inhibitor (dabigatran). The studies (RE-LY, ROCKET-AF, ARISTOTLE, AVERROES) provide promising results for the new agents, including higher efficacy and a significantly lower incidence of intracranial bleeds compared with warfarin or aspirin. The new drugs show similar results in secondary as well as in primary stroke prevention in patients with AF. Apixaban was demonstrated to be clearly superior to aspirin and had the same rate of major bleeding complications. Meta-analyses show that the novel anticoagulants are superior to warfarin for the reduction of stroke, major bleeding and intracranial bleeds. New anticoagulants add to the therapeutic options for patients with AF, and offer a number of advantages over warfarin, for both the clinician and patient, including a favorable bleeding profile and convenience of use. Aspirin is no longer an option in secondary stroke prevention in patients with atrial fibrillation. Consideration of these new anticoagulants will improve clinical decision making.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Guidelines as Topic; Humans; Intracranial Hemorrhages; Morpholines; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Thromboembolism; Warfarin

Venous thromboembolism (VTE) represents a common source of morbidity and mortality among patients with malignant disease. In this specific setting, the treatment of VTE is challenging as cancer patients display a high tendency to develop recurrent VTE, as well as anticoagulant-related bleeding complications. Low-molecular-weight heparins have been demonstrated to be more effective in the long-term prevention of recurrent VTE in cancer patients compared with conventional treatment with vitamin K antagonists. A limitation of this therapeutic approach includes the long-term requirement of daily subcutaneous injections, which may be burdensome to patients. Over the past decade, several novel oral anticoagulants have emerged, which can be administered in fixed doses without the need for monitoring. Clinical trials evaluating these agents for treatment in the general VTE population yielded promising results. This review summarizes the current management of cancer-associated VTE, overviews the trials that investigated the novel anticoagulant drugs for the treatment of acute VTE and discusses the potential of these novel agents for use in cancer patients.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Drug Administration Schedule; Heparin, Low-Molecular-Weight; Humans; Morpholines; Neoplasms; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiophenes; Treatment Outcome; Venous Thromboembolism; Warfarin

New oral anticoagulants, acting either as direct factor-Xa or thrombin inhibitors, have been evaluated for the acute and long-term treatment of venous thromboembolism (VTE). Dabigatran and rivaroxaban are as effective as conventional therapy (heparin/vitamin K antagonists) without safety concerns. Rivaroxaban allows a single-drug regimen even in patients with pulmonary embolism, while dabigatran requires 5-7 days of initial heparin treatment. The results of clinical trials with apixaban and edoxaban will become available in the coming months. Rivaroxaban, apixaban and dabigatran are more effective than placebo for the extended treatment of VTE. Apixaban is effective in both therapeutic and prophylactic doses. Considering both efficacy and bleeding complications, all these agents have a favorable net clinical benefit. Dabigatran is as effective and safe as warfarin for the extended treatment of VTE. It is conceivable that the new oral anticoagulants will become the standard therapy for VTE in the next years.

Topics: Administration, Oral; Adult; Aged; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Drug Administration Schedule; Humans; Middle Aged; Morpholines; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiazoles; Thiophenes; Venous Thromboembolism; Warfarin

The direct thrombin inhibitor, dabigatran, and the selective factor Xa inhibitors, rivaroxaban and apixaban, are new oral anticoagulants that are approved in many countries for prevention of venous thromboembolism in patients undergoing elective hip or knee arthroplasty. All have a rapid onset of action, a low potential for food and drug interactions and a predictable anticoagulant effect that obviates the need for routine coagulation monitoring. These agents offer a convenient alternative to conventional anticoagulant drug regimens, including parenteral low-molecular-weight heparins and fondaparinux, and oral adjusted-dose vitamin K antagonists, for the prevention of venous thromboembolism in this surgical setting. This review summarizes the pharmacology, clinical trial results, bleeding risk and practical use of these new oral anticoagulants in clinical orthopaedic practice. Potential issues to be considered when using these oral anticoagulants include renal impairment, potential drug interactions, neuraxial anaesthesia and management of bleeding.

Topics: Administration, Oral; Anticoagulants; Arthroplasty, Replacement; Benzimidazoles; beta-Alanine; Dabigatran; Drug Administration Schedule; Heparin, Low-Molecular-Weight; Humans; Morpholines; Postoperative Hemorrhage; Pulmonary Embolism; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiophenes; Venous Thromboembolism; Warfarin

The risk of venous thrombosis extends for an indeterminate length of time following admission to hospital with a medical or surgical condition. Observational studies in surgery show this risk extends for months and perhaps more than one year, for medical patients the risk extends for at least several weeks. Large bodies of evidence support the heightened risk status of hospitalised surgical and medical patients, and that prophylactic measures significantly reduce the risk of thrombosis. Extending thromboprophylaxis for 4-6 weeks with anticoagulants both old and new has been shown to be efficacious and safe in surgical patients. However in populations of medical patients although prolonged anticoagulant thromboprophylaxis has been shown to be efficacious it also results in more bleeding and the risk benefit is not clear. Hence no therapies are approved for prolonged thromboprophylaxis in medical patients. In this area there have been one phase III study of low molecular weight heparin and two completed phase III studies of NOACs. This article briefly summarises our understanding of the background to preventing venous thromboembolism in hospitalised medical patients and reviews the details of the studies using NOACs.

Topics: Administration, Oral; Aged; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Drug Administration Schedule; Enoxaparin; Humans; Morpholines; Postoperative Hemorrhage; Pulmonary Embolism; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Surgical Procedures, Operative; Thiophenes; Venous Thromboembolism; Warfarin

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

The new oral anticoagulants (NOACs) dabigatran etexilate, rivaroxaban, and apixaban have been extensively studied for prevention and treatment of venous thromboembolic disease and for stroke prevention in atrial fibrillation. Elderly patients have the highest incidence of thrombotic complications but also have the highest risk of anticoagulant associated bleeding. In this review we critically examine the balance between risks and benefits of NOACs compared with vitamin K antagonists in elderly patients enrolled in phase 3 randomized controlled trials for the management of venous thrombosis and stroke prevention in atrial fibrillation. Results show that the favourable balance between risks and benefits of NOACs is preserved in the elderly population.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Benzimidazoles; Dabigatran; Drug Administration Schedule; Humans; Intracranial Hemorrhages; Morpholines; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Venous Thromboembolism; Vitamin K; Warfarin

Atrial fibrillation (AF) is a common arrhythmia and the leading cause of stroke, an event with high human and economic burden. Novel oral anticoagulants have been approved in many markets as alternatives to warfarin for stroke prevention in patients with AF - dabigatran etexilate, apixaban and rivaroxaban. Given the high burden of AF, and given that new treatments can more effectively prevent stroke than warfarin, but at higher drug cost, there has been a need for systematic evaluation of the costs and benefits of these new treatments. In this study, we summarize the findings of a systematic literature review on the cost-effectiveness of the new oral anticoagulants. We find that there is substantial heterogeneity between the studies and their numerical findings, despite using a common set of four trials for their clinical inputs. However, there is broad consensus among them that each of the novel oral anticoagulants is cost-effective versus warfarin or aspirin.

Topics: Administration, Oral; Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Benzimidazoles; Cost-Benefit Analysis; Dabigatran; Drug Administration Schedule; Humans; Intracranial Hemorrhages; Morpholines; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Venous Thromboembolism; Warfarin

To summarise and compare the efficacy and safety of various oral anticoagulants (dabigatran, rivaroxaban, apixaban, and vitamin K antagonists) and antiplatelet agents (acetylsalicylic acid) for the secondary prevention of venous thromboembolism.. Systematic review and network meta-analysis.. Literature search using Medline (1950 to present), Embase (1980 to present), and the Cochrane Register of Controlled Trials using the OVID interface. Publications from potentially relevant journals were also searched by hand.. Randomised controlled trials of patients receiving anticoagulants, antiplatelet drugs, or placebo or observation for secondary prevention of venous thromboembolism. Selected outcomes were rates of recurrent venous thromboembolism and major bleeding. Two reviewers independently extracted data onto standardised forms.. 12 articles met our inclusion criteria, with 11,999 patients evaluated for efficacy and 12,167 for safety. All treatments reduced the risk of recurrent venous thromboembolism. Compared with placebo or observation, vitamin K antagonists at a standard adjusted dose (target international normalised ratio 2.0-3.0) showed the highest risk difference (odds ratio 0.07; 95% credible interval 0.03 to 0.15) and acetylsalicylic acid showed the lowest risk difference (0.65; 0.39 to 1.03). Risk of major bleeding was higher with a standard adjusted dose of vitamin K antagonists (5.24; 1.78 to 18.25) than with placebo or observation. Fatal recurrent venous thromboembolism and fatal bleeding were rare. Detailed subgroup and individual patient level data were not available.. All oral anticoagulants and antiplatelet agents investigated in this analysis were associated with a reduced recurrence of venous thromboembolism compared with placebo or observation, although acetylsalicylic acid was associated with the lowest risk reduction. Vitamin K antagonists given at a standard adjusted dose was associated with the greatest risk reduction in recurrent venous thromboembolism, but also the greatest risk of major bleeding.

Topics: Anticoagulants; Aspirin; Benzimidazoles; beta-Alanine; Dabigatran; Hemorrhage; Humans; Morpholines; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Recurrence; Rivaroxaban; Thiophenes; Venous Thromboembolism; Vitamin K

Dabigatran, rivaroxaban and apixaban are three new oral anticoagulants that have recently been approved in Norway. The aim of this article is to provide an overview of the mechanisms of action, the most important indications and practical advice on the use of these drugs.. The review is based on published phase 3 studies, a literature search in PubMed and the authors' clinical experience.. Indications for use of the new anticoagulants include thromboprophylaxis after total hip and knee replacement surgery (all three), prevention of stroke and systemic embolism in non-valvular atrial fibrillation (all three), treatment of acute venous thrombosis and secondary prophylaxis after venous thrombosis (currently only rivaroxaban). For the aforementioned indications, these drugs have proven to be non-inferior to standard established anticoagulation therapy. For atrial fibrillation, all three drugs have also shown a lower incidence of intracranial bleeding compared with standard treatment.. It is important to limit the use of these drugs to approved indications, to select patients who show good compliance, to rule out contraindications and to identify drug interactions. Monitoring of coagulation is not required, but patients should be followed up regularly to detect conditions that may lead to changes in the expected efficacy or safety.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Humans; Medication Adherence; Morpholines; Practice Guidelines as Topic; Pulmonary Embolism; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism; Venous Thrombosis

Topics: Anticoagulants; Aspirin; Benzimidazoles; Clopidogrel; Dabigatran; Emergencies; Enoxaparin; Fondaparinux; Heparin; Humans; Morpholines; Platelet Aggregation Inhibitors; Platelet Transfusion; Polysaccharides; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Surgical Procedures, Operative; Thiophenes; Ticlopidine; Warfarin

Oral anticoagulant therapy, either with vitamin K antagonists (VKAs) or with novel oral anticoagulants such as dabigatran, rivaroxaban, and apixaban, is the mainstay for thromboprophylaxis in patients with atrial fibrillation (AF). Thromboembolic risk factors associated with AF and risk factors for bleeding associated with oral anticoagulant therapy are largely the same, and bleeding risk very rarely outweighs individual benefit of thrombosis prevention, thus resulting in positive net clinical benefit of oral anticoagulant therapy in almost all AF patients. Prevention of AF‑related thromboembolic events most commonly requires long‑term oral anticoagulant therapy. Over time, various clinical situations may occur in a given patient (e.g., a need for an urgent surgery or invasive intervention, acute stroke, etc.), which may require a temporary or permanent modification of anticoagulant therapy regardless of which anticoagulant drug has been used. This may be particularly challenging for physicians because many issues regarding optimal use of oral anticoagulant drugs in specific clinical situations still remain to be solved. In this review article, we discuss the periprocedural management of oral anticoagulant therapy, bridging, transition to another oral anticoagulant, the occurrence of acute stroke in a patient already taking an oral anticoagulant, and decision when it is safe to resume oral anticoagulation therapy after stroke. We summarize the available evidence and current (and future) approaches to oral anticoagulation management in such clinical situations.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Catheter Ablation; Dabigatran; Drug Administration Schedule; Fibrinolytic Agents; Forecasting; Humans; Morpholines; Percutaneous Coronary Intervention; Postoperative Care; Postoperative Hemorrhage; Premedication; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Thromboembolism; Warfarin

Warfarin has been the sole oral anticoagulant used in the management of thromboembolic disorders for over 60 years. Target-specific oral anticoagulants (TSOAs) have recently emerged as alternatives to warfarin, because they do not require laboratory monitoring. Nevertheless, with the rising use of TSOAs, there is growing concern among clinicians regarding management of bleeding in patients taking them. Unlike warfarin, there is no antidote or reversal agent for TSOAs. This review summarizes recent developments and attempts to provide a systematic approach to patients on TSOAs presenting with bleeding complications.. Currently, data involving clinical management of TSOAs are limited and primarily based on ex-vivo or animal models using hemostatic agents with uncertain implications in bleeding patients. There is a pressing need for randomized clinical trials evaluating the safety and efficacy of hemostatic agents.. Without evidence-based guidelines for TSOA management, appropriate patient care requires an understanding of TSOA pharmacology, their effect on coagulation tests and, hence, a correct interpretation of test results, as well as a systematic approach to bleeding complications.

Topics: Anticoagulants; Antithrombins; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Hemorrhagic Disorders; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes

Venous thromboembolism is a common cause of morbidity and mortality among patients undergoing elective orthopedic surgery. Due to the high incidence of venous thromboembolism in this setting, perioperative anticoagulation is the recommended approach for thromboprophylaxis. Low molecular weight heparin (LMWH), fondaparinux and warfarin are the agents commonly used for thromboprophylaxis. The well-recognized limitations of warfarin and the inconvenience and discomfort associated with the subcutaneous administration of low molecular weight heparin and fondaparinux inspired intense investigation to develop novel oral anticoagulants (NOACs) with more predictable pharmacokinetics, fewer drug interactions and no need for regular laboratory monitoring. Three NOACs have been demonstrated to be effective for thromboprophylaxis after total hip arthroplasty (THA) and total knee arthroplasty (TKA) in large randomized controlled trials. Here we review the pharmacology of rivaroxaban, dabigatran, and apixaban, summarize the major clinical trials of these agents in thromboprophylaxis after THA and TKA, and discuss the clinical factors to be considered by providers when selecting a NOAC for their patients.

Topics: Administration, Oral; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Humans; Morpholines; Postoperative Complications; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism

Within the past 5 years, the oral anticoagulants rivaroxaban, apixaban, and dabigatran etexilate have been approved for the prevention of venous thromboembolism in adult patients after elective hip or knee arthroplasty in the European Union and many other countries worldwide. These agents differ from the previously available anticoagulants because they selectively and directly inhibit a single factor in the coagulation cascade-rivaroxaban and apixaban inhibit Factor Xa, and dabigatran inhibits Factor IIa (thrombin)-potentially enhancing the predictability of their anticoagulant effect. Currently, although some guidelines provide recommendations for the use of rivaroxaban, dabigatran etexilate, and apixaban in clinical practice, there are still questions regarding the optimal practical management of patients receiving these agents. This article briefly reviews the practical limitations associated with conventional anticoagulants, discusses potential issues with the practical management of the newer oral anticoagulants, and provides clinical experience from a single institution where rivaroxaban and dabigatran etexilate have been used within their approved indications.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Benzimidazoles; Blood Coagulation Tests; Clinical Trials, Phase III as Topic; Contraindications; Dabigatran; Drug Administration Schedule; Drug Interactions; Drug Monitoring; Hematoma, Epidural, Spinal; Humans; Morpholines; Platelet Aggregation Inhibitors; Postoperative Complications; Postoperative Hemorrhage; Postoperative Nausea and Vomiting; Practice Guidelines as Topic; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism

To review pharmacokinetic and pharmacodynamic drug-drug interactions (DDIs) involving new oral anticoagulants for atrial fibrillation.. A literature search was conducted via PubMed and the Cochrane database to identify DDI studies using the terms drug interactions, dabigatran, rivaroxaban, and apixaban. Prescribing information and Food and Drug Administration briefing documents were used to supplement published data.. English publications identified on Medline from 2005 up to August 2013 and US prescribing information for approved oral anticoagulants.. Articles reviewed focused on drugs affecting the permeability glycoprotein (P-gp) efflux transporter protein and/or cytochrome P (CYP) 450 3A4 enzymes, and pharmacodynamic DDIs when drugs are administered concomitantly. Phase I DDI studies have reported pharmacokinetic DDIs mediated by P-gp alone (dabigatran etexilate) or in combination with CYP3A4 enzymes (rivaroxaban and apixaban). Dabigatran etexilate should not be administered with any P-gp inhibitor in patients with severe renal impairment. Briefing documents indicate that rivaroxaban and apixaban should not be used with drugs that are strong inhibitors of both P-gp and CYP3A4. DDI studies involving rifampicin suggest that rivaroxaban and apixaban should be avoided when strong inducers of P-gp and CYP3A4 are used concurrently. Concomitant use of apixaban and strong dual inhibitors of P-gp and CYP3A4 should be avoided or the dose reduced. Five randomized clinical trials report additive effects with rivaroxaban, dabigatran, and apixaban when used concomitantly with antiplatelet agents; bleeding rates have been found to be higher, especially with dual antiplatelet therapy.. Awareness of drugs that alter the function of the P-gp efflux transporter protein and CYP3A4 enzymes and provide additive effects should enable prescribers to anticipate and avoid potential DDIs involving the new oral anticoagulants. To this end, briefing documents and prescribing information have applied cautionary measures for individuals treated with these newer anticoagulants.

Topics: Anticoagulants; ATP Binding Cassette Transporter, Subfamily B, Member 1; Atrial Fibrillation; Benzimidazoles; Cytochrome P-450 Enzyme System; Dabigatran; Drug Interactions; Drug Therapy, Combination; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes

Atrial fibrillation is a commonly encountered problem in the outpatient setting. This article presents an overview of the outpatient management of oral anticoagulation for the prevention of stroke and systemic embolism in the setting of atrial fibrillation. Results of recent clinical trials demonstrating the efficacy and safety of 3 of the new target-specific oral anticoagulants are reviewed. Discussion includes determining patient candidates for the newer agents and consideration for choice of agent. Advantages and disadvantages to using these newer agents are presented, as are dosing adjustments for renal and hepatic impairment.

Topics: Ambulatory Care; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Warfarin

Novel oral anticoagulants (NOAC) such as the direct thrombin inhibitor, dabigatran, and oral factor Xa inhibitors, rivaroxaban and apixaban, have recently approved for prevention of stroke in nonvalvular atrial fibrillation (NVAF). Phase III trials have compared each of these agents to warfarin. Dabigatran was more efficacious than warfarin in reducing the risk of stroke when given at a dose of 150 mg BID to patients with NVAF. Rivaroxaban 20 mg QD was superior to warfarin in on-treatment analysis. Apixaban 5 mg BID was also found to be superior to warfarin in reducing stroke in NVAF patients. Of note, the rate of hemorrhagic stroke was much smaller in the patients treated with NOAC than those with warfarin. NOAC offer a good therapeutic option for prevention of stroke in NVAF patients.

Topics: Administration, Ophthalmic; Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cerebral Infarction; Clinical Trials, Phase III as Topic; Dabigatran; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Warfarin

The new oral anticoagulants are approved for a variety of clinical syndromes, including the prevention of stroke in atrial fibrillation, acute coronary syndromes, treatment of venous thromboembolism (VTE), and prevention of venous thrombosis after total joint surgery or hip fracture. Published guidelines have differing recommendations on the safe interval between discontinuation of the anticoagulant and performance of neuraxial procedures and between the interventional procedure and redosing of the drug. While two to three half-life intervals might be acceptable in patients who are at high risk for VTE or stroke, an interval of four to six half-lives between discontinuation of the drug and neuraxial injections is probably safer in most patients at low risk of thrombosis. In those with renal disease, the interval should be based on creatinine clearance. After a neuraxial procedure or removal of an epidural catheter, anticoagulants can be resumed within 24-48 h in most patients, but they can be taken sooner in patients who are at higher risk for VTE or stroke, that is, 24 h minus the time to peak effect of the drug. The new antiplatelet drugs prasugrel and ticagrelor should be stopped 7 or 5 days, respectively, before a neuraxial injection and can be restarted 24 h later. In selected situations, laboratory monitoring of the anticoagulant effect is appropriate, and reversal agents are suggested when there is a need to rapidly restore haemostatic function.

Topics: Administration, Oral; Anesthesia, Conduction; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Humans; Morpholines; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thrombosis

Topics: Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Brain Infarction; Dabigatran; Humans; Intracranial Embolism; Ischemic Attack, Transient; Morpholines; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Risk Factors; Rivaroxaban; Stroke; Thiophenes; Vitamin K

Treatment with vitamin K antagonists are subject to a common iatrogenic mainly characterized by hemorrhagic stroke. Their narrow therapeutic range associated with variability largely explains this phenomenon. New oral anticoagulants (NOAC) are now available. dabigatran (Pradaxa®) is a direct and specific thrombin inhibitor. It is excreted mainly by the kidney and is the only which can be dialyzed. Rivaroxaban (Xarelto®) and apixaban (Eliquis®) are factor X activated direct inhibitors. They are highly bound to plasma proteins and are metabolized mainly by the liver, via CYP3A4. All NOAC are substrates of P-glycoprotein (P-gp). Due to pharmacological changes, some populations at risk were identified: patients with hepatic impairment, renal impairment, elderly patients or low weight. Some pharmacokinetic or pharmacodynamic drug interactions alter the concentration and the expected impact of NOAC. The NOAC does not require biological monitoring. They interfere with the routine coagulation tests which should be interpreted with caution. Specific tests exist and can be used in case of emergencies. Currently, no antidote is available. The new oral anticoagulant look promising in the elderly. However, certain rules must be followed to reduce the risk of iatrogenic.

Topics: Administration, Oral; Aged; Anticoagulants; Benzimidazoles; beta-Alanine; Cerebral Infarction; Dabigatran; Dose-Response Relationship, Drug; Drug Interactions; Drugs, Investigational; Humans; Iatrogenic Disease; Intracranial Hemorrhages; Morpholines; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Stroke; Thiophenes; Vitamin K

Atrial fibrillation treatment relies on anticoagulation therapy that reduces the risk of stroke. Vitamin K antagonists (VKA) were the only oral anticoagulant drugs for more than 50 years, but they are difficult to manage especially in the elderly. In France, VKA are the main cause of iatrogenic hospitalizations with about 17,000 hospitalizations per year and around 4,000 to 5,000 deaths per year. Pharmacologic properties of VKA, especially the narrow therapeutic margin explain the complexity of their management. Several studies have shown that patients treated with VKA were on average only 50% of the time with an INR in the therapeutic range. In other words, patients are, half of the time, either-under treated or over-treated. Within this framework, development of new oral anticoagulant drugs appeared necessary, in order to obtain drugs with larger therapeutic margin and a better risk/benefit profile than VKA. Three large randomized clinical trials including almost 50,000 patients with 20,000 subjects over 75 years old and 8,000 over 80 years old, show a better risk/benefit profile of the new oral anticoagulants (NOAC) than VKA, characterized by a 50% reduction of cerebral hemorrhages, 22% reduction of stroke and 12% reduction of total mortality. Meanwhile, their renal elimination and the lack of control of the biological efficacy need to be taken into account for their prescription. Renal failure (estimated glomerular filtration rate according to Cockcroft formula < 30 mL/min) contraindicates their use. Their half-life is shorter than that of VKA and the biological monitoring is not available, thus a good adherence to the treatment is important. Studies specifically conducted among geriatric older population with poly-pathologies and frail are therefore needed to evaluate tolerance of NOAC in real life conditions.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cerebral Hemorrhage; Dabigatran; Drugs, Investigational; Half-Life; Humans; Intracranial Embolism; Metabolic Clearance Rate; Morpholines; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Risk Assessment; Rivaroxaban; Stroke; Thiophenes; Vitamin K

The novel oral anticoagulant drugs, comprising dabigatran, rivaroxaban, and apixaban, have emerged as compelling alternatives to vitamin K antagonists for stroke prevention in atrial fibrillation, and low‑molecular‑weight heparin for thromboprophylaxis following hip and knee arthroplasty. Rivaroxaban has also been approved for treatment of venous thromboembolism. However, the role of these drugs for the management of patients with an acute coronary syndrome (ACS) is less certain. The purpose of this review was to summarize the randomized trials evaluating novel oral anticoagulants in patients with an ACS and consider the reasons why these drugs have not been incorporated into routine clinical practice. In addition, the situation involving rivaroxaban, which has been approved for use in patients with an acute coronary syndrome in Europe but not in North America, is discussed.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes

Atrial Fibrillation (AF) is the most frequent cardiac arrhythmia and its incidence increases with age reaching a 10% prevalence in the oldest old. Patients with AF have a five-fold increase in the risk of stroke. Current guidelines on AF management recommend the prescription of oral anticoagulant therapy in patients at medium and high risk of thromboembolic events. Advanced age is a risk factor for stroke in AF, but despite clear evidences a high rate of OAT under prescription is reported and particularly in the oldest old. Among the main causes of this phenomenon an enhanced risk of bleeding is often reported: this due to several factors: risk of falls, the presence of comorbidity and polifarmacy and a reduction in compliance and adherence that are common in the elderly. In recent years the international scenario in the management of OAT has significantly changed since the introduction of the new oral anticoagulants (NOA): Dabigatran, a direct thrombin inhibitor, and two oral factor Xa inhibitors Rivaroxaban and Apixaban, which have all been tested in randomized clinical trial (RELY, ROCKET-AF e ARISTOTLE) which have demonstrated non inferiority compared to warfarin in the prevention of thromboembolic events with an optimal safety profile. NOA could be an important therapeutic opportunity for stroke prevention in elderly patients with AF even if the substantial differences in mean age, anthropometric measures and comorbidity of the patients enrolled in these trials compared with those of the real world setting, oblige some caution and discussion.

Topics: Administration, Oral; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes

As acute coronary syndrome (ACS) becomes more common nationwide and current anticoagulation regimens used in patients with ACS continue to possess their shortcomings, the need for new anticoagulants is on the rise. Although heparin and warfarin are used effectively in patients with ACS, they both have significant side effects and delivery issues. New factor Xa inhibitors offer an oral alternative that functions early in the coagulation cascade. The role of these new drugs in ACS is explored here. Electronic search strategies were used to collect reviews, randomized controlled trials, and other studies. Databases used included Medline and Cochrane Library and hand selection. Sources selected were limited to those that discussed factor Xa inhibitors in the context of ACS. Selected studies were then assessed for quality and relevance and those deemed relevant included for analysis. Some of the factor Xa inhibitors such as rivaroxaban offer anticoagulation as effective as, if not more effective, heparin and warfarin with lower risks of bleeding and other adverse effects such as heparin-induced thrombocytopenia. Many of these new agents also come in oral form, making them easy for patients to manage and use daily.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Cyclic N-Oxides; Factor Xa Inhibitors; Fondaparinux; Heparin; Humans; Morpholines; Naphthalenes; Polysaccharides; Propionates; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Treatment Outcome; Warfarin

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide with a prevalence that has now reached pandemic levels as a consequence of the rapid modernization of the developing world. Its presentation as an acute coronary syndrome (ACS) is a frequent reason for hospital admission and of profound implications for personal, societal and global health. Despite improvements in the management of ACS with anti-platelet and anticoagulant therapy and revascularization techniques, many patients continue to suffer recurrent ischemic events. The need to reduce future cardiovascular events has led to the development of novel therapies to prevent coronary thrombosis, targeting thrombin-mediated pathways. These include direct Xa inhibitors (apixaban, rivaroxaban and darexaban), direct thrombin inhibitors (dabigatran) and PAR 1 antagonists (vorapaxar and atopaxar). This article critically reviews the comparative mechanisms of action, the risks and benefits, together with the clinical evidence base for the use of these novel oral agents in the management of ACS patients.

Topics: Acute Coronary Syndrome; Administration, Oral; Animals; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiophenes

The new oral anticoagulants (NOAs) dabigatran, rivaroxaban, and apixaban have proved effective and safe when used in clinical trials, without a need to adjust the dose in response to laboratory testing. This demonstrated efficacy does not necessarily mean that the laboratory, considered the mainstay for the management of the old anticoagulants, will no longer play a role in treatment with NOAs.. Laboratories are involved in the management of anticoagulants in 2 ways. The first, monitoring, implies laboratory testing to assess the drug's effect and to adjust the dosage to maintain anticoagulation within the therapeutic interval. This consideration applies to the old drugs. The second way, measurement, implies laboratory evaluations of drug effect to determine whether patients are under- or over-anticoagulated, information that can be useful for decision-making in special circumstances. The latter applies to NOAs.. Measurements of the effect of NOAs are indicated in several situations: (a) patients with adverse events (i.e., thrombotic/hemorrhagic), particularly those who present with overdosage owing to excessive drug intake or decreased clearance; (b) patients undergoing surgical procedures for ensuring that no residual drug remains in the circulation; (c) patients requiring anticoagulation reversal because of life-threatening hemorrhage; (d) patients with renal insufficiency, who are likely to accumulate the drug in the circulation; (e) patients with liver failure, because NOAs are metabolized by the liver; (f) patients taking other drugs that might increase/decrease the effects of NOAs via drug-drug interactions. The choice of tests is based on such characteristics as availability, linearity of the dose-response curve, standardization, and responsiveness to increasing drug dosage. Practitioners need to be aware that NOAs can interfere with the measurement of common hemostasis parameters.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Blood Coagulation Tests; Dabigatran; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Hemostasis; Humans; Liver Diseases; Morpholines; Pyrazoles; Pyridones; Renal Insufficiency; Rivaroxaban; Thiophenes

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

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

Novel oral anticoagulants that directly inhibit thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban) are currently available for prevention of venous thromboembolism (VTE) after orthopaedic surgery, treatment of acute VTE, and prevention of arterial thromboembolism in non-valvular atrial fibrillation. These agents offer advantages over VKAs, including rapid onset, shorter half-lives, fewer drug interactions, and lack of need for routine monitoring. However, there are no established agents to reverse their anticoagulant effect. We review the risk of bleeding with the novel oral anticoagulants and the limitations of conventional coagulation assays for measuring anticoagulant effect. We provide an approach to the management of patients with bleeding complications with evidence for various interventions for reversal, where available.

Topics: Acute Disease; Administration, Oral; Aged; Anticoagulants; Antithrombins; Benzimidazoles; beta-Alanine; Blood Coagulation Tests; Dabigatran; Drug Therapy, Combination; Factor Xa Inhibitors; Hemorrhage; Hemostatics; Humans; Morpholines; Plasma; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Renal Dialysis; Renal Insufficiency; Risk Factors; Rivaroxaban; Thiophenes

Three new oral anticoagulant agents were tested versus warfarin in separate, large phase III randomized clinical trials for prevention of any stroke and systemic embolism in atrial fibrillation. Dabigatran, a direct thrombin inhibitor, is at 110 mg bid non-inferior and at 150 mg bid superior to warfarin; rivaroxaban, a factor X inhibitor, is also non-inferior, and apixaban, also a factor X inhibitor, is superior to warfarin on the same efficacy end point. Statistical analysis of subgroups does not suggest, for any of the tested drugs, major differences in relation to different risk levels and history of previous stroke/TIA. This re-appraisal of data was undertaken in search for possible additional information, by considering the absolute differences in efficacy and safety events versus warfarin and the corresponding efficiency and number needed to treat, also with regard to secondary versus primary prevention. By this approach, it appears that for all drugs, equivalence or advantage versus warfarin on the efficacy end point is largely driven by a reduction in hemorrhagic rather than ischemic strokes. Dabigatran shows a balanced effect on ischemic and hemorrhagic strokes, and apixaban is most effective in sparing intracranial bleeding versus warfarin. In secondary prevention, better efficiency is shown by dabigatran 150 and apixaban, versus rivaroxaban, despite the higher proportion of post-stroke/TIA patients (55 %) in the ROCKET AF trial of rivaroxaban seemed to favor better results of this drug in secondary prevention. These and other results of our approach should not be directly translated into clinical practice. They may supply useful suggestions to be subsequently tested in specific trials, although head-to-head comparative studies of the three drugs remain unlikely.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Venous Thrombosis

Data comparing traditional and novel anticoagulants are reviewed, and the potential use of new oral agents for the prevention and treatment of venous thromboembolism (VTE) is assessed.. Practical challenges in using traditional anticoagulants are well established and have led to the search for new oral agents. Apixaban, rivaroxaban, and dabigatran etexilate are new oral anticoagulants that may offer simpler, more effective, and safer treatment and prevention of VTE, which may increase adherence to such therapy, improve outcomes, and decrease overall health care costs. Their immediate onset of anticoagulant effect, ease of oral administration, and lack of needed regular anticoagulation monitoring are of interest in the medical and pharmacy communities. However, in the treatment and prevention of VTE, more data will be needed to determine their ultimate place in therapy. This review is intended to provide pharmacists with an objective overview of practical considerations that can help them understand the clinical data to facilitate their selection of anticoagulants.. Apixaban, rivaroxaban, and dabigatran etexilate are new oral agents for the prevention and treatment of VTE.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Benzimidazoles; Dabigatran; Drug Monitoring; Evidence-Based Medicine; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Treatment Outcome; Venous Thromboembolism

Effective prophylaxis and treatment of thromboembolic disorders remain suboptimal in many healthcare systems, partly owing to limitations of traditional anticoagulants. New oral anticoagulants have been developed and among these, rivaroxaban, apixaban and dabigatran etexilate are in the most advanced stage of clinical development.. A literature search using the PubMed and ClinicalTrials.gov databases was performed to identify English-language publications. The search was performed up to 31 December 2011 with the terms rivaroxaban OR Xarelto, apixaban OR Eliquis and dabigatran OR Pradaxa. Ongoing, completed and published phase III randomised controlled trials were selected as the primary source of information for the clinical development programme of each drug.. The new oral agents demonstrate several advantages over traditional anticoagulants, including administration at fixed doses and no requirement for routine coagulation monitoring On the basis of phase III clinical trials, rivaroxaban, apixaban and dabigatran etexilate have been approved in many countries for the prevention of venous thromboembolism after hip and knee replacement surgery. Dabigatran etexilate and rivaroxaban have also been approved for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation in Europe and the US. In addition, rivaroxaban has been approved in Europe for the treatment of acute deep vein thrombosis and prevention of recurrent venous thromboembolism. Approval of these agents and postapproval monitoring of their safety and efficacy will have implications for primary care.. Rivaroxaban, apixaban and dabigatran etexilate offer the possibility of simplified prevention and treatment strategies for thromboembolic disorders in the outpatient setting.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Benzimidazoles; beta-Alanine; Clinical Trials, Phase III as Topic; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Venous Thromboembolism

The direct factor Xa (FXa) inhibitors rivaroxaban, apixaban and edoxaban, and the thrombin inhibitor dabigatran etexilate (dabigatran) have gained approval for use in several indications, most notably for the prevention and treatment of venous thromboembolism (VTE) and for the prevention of stroke in patients with atrial fibrillation. Hepatic impairment can affect the disposition of these anticoagulants considerably not only because of the hepatic metabolism of the direct FXa inhibitors but also because moderate to severely impaired hepatic function will affect coagulation. This review describes the key pharmacological properties of novel oral anticoagulants with special attention to patients with impaired hepatic function. In subjects with moderately impaired liver function (i.e. Child-Pugh classification B), the area under the plasma concentration-time curve (AUC) of rivaroxaban (10 mg single dose) is increased by 2.27-fold, which is paralleled by an increase in FXa inhibition. The AUC of apixaban (5 mg single dose) is increased by 1.09-fold, whereas the AUC of edoxaban (15 mg single dose) is decreased by 4.8 % and the AUC of dabigatran (150 mg single dose) is decreased by 5.6 %. Specific labelling restrictions for rivaroxaban, apixaban and dabigatran regarding impaired hepatic function are based on both the Child-Pugh classification and liver-related exclusion criteria applied in pivotal clinical trials. Rivaroxaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients classified as Child-Pugh B and C. Apixaban can be used with caution in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment or in patients with alanine aminotransferase and aspartate aminotransferase levels >2× upper limit of normal (ULN). Apixaban is not recommended in patients with severe hepatic impairment and is contraindicated in those with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Dabigatran is not recommended in patients with elevated liver enzymes (>2× ULN). Dabigatran is contraindicated in patients with hepatic impairment or liver disease expected to have any impact on survival. Currently, edoxaban is not available in the US or European markets. However, the Japanese label did not restrict use in hepatic dysfunction but advises care in patients with severe hepatic impairment.

Topics: Absorption; Anticoagulants; Benzimidazoles; Dabigatran; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Humans; Liver Diseases; Metabolic Clearance Rate; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Thrombin; Tissue Distribution; Venous Thromboembolism

After the introduction of warfarin, long-term oral anticoagulation treatment remained unchanged for more than 50 years. Most recently, with the development and approval of new oral anticoagulants, the treatment of medical conditions that require thrombosis prophylaxis and long-term anticoagulation has become more complex. In the case of venous thromboembolism (VTE) prevention after orthopedic surgery, the new oral agents will be less costly than the parenteral alternative. In other settings (such as atrial fibrillation or treatment of acute VTE), the new agents will offer additional convenience at higher cost, but the degree to which they will reduce clinically important events such as thrombosis or bleeding will be limited, especially for patients on optimally controlled warfarin. As the use of the new oral anticoagulants becomes more widespread, it will be important for all clinicians to have a basic understanding of their pharmacology, advantages, and limitations. Although the need to measure or reverse the effect of these drugs will arise infrequently, clinicians--especially hematologists--will desire evidence-based recommendations about how to manage such scenarios, which will require research studies.

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

Atrial fibrillation (AF) is an important cause of ischemic stroke and is the underlying cause of > 20% of all strokes, with increasing age being a risk factor. Until recently, warfarin was the only available oral anticoagulant used to decrease this risk in patients with AF. However, there are several disadvantages of warfarin use, such as the requirement for monitoring the international normalized ratio, its wide range of drug-food interactions, and its narrow therapeutic index. Thus, there has been a strong impetus for the development of newer oral anticoagulants with predictable pharmacokinetics that obviate the need for monitoring the international normalized ratio. The US Food and Drug Administration has approved a direct thrombin inhibitor (dabigatran) and 2 factor Xa inhibitors (rivaroxaban and apixaban) for stroke prevention in patients with nonvalvular AF. There are several other new oral anticoagulant agents on the horizon, including the factor Xa inhibitor edoxaban. This review article discusses the pharmacological properties, clinical trial data, and practical issues associated with the use of these novel oral anticoagulants.

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

Thromboembolic disease, both arterial and venous, is a major cause of morbidity and mortality in developed countries. The new anticoagulants exert their action by selective, direct and reversible inhibition of a single coagulation factor. Although the results of several phase III trials have demonstrated the safety and efficacy of these drugs, their mechanism of action, as well as the pharmacodynamics and pharmacokinetics of these drugs, need to be understood for their correct use. The present review discusses the features of the new anticoagulants whose clinical development is more advanced, both those designed to block active factor X, such as rivaroxaban or apixaban, and those designed to block thrombin (also active factor II): dabigatran.

Topics: Anticoagulants; Benzimidazoles; beta-Alanine; Blood Coagulation; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes

Patients undergoing a total hip or total knee arthroplasty are at high risk of thromboembolism in the postoperative period and after hospital discharge; consequently, clinical guidelines recommended thromboprophylaxis for 10-35 days. Although improved surgical techniques and widespread use of anticoagulants have substantially reduced the incidence of thromboembolic events, venous thromboembolic disease is still a dangerous complication and, in these patients, pulmonary embolism remains the main cause of death. Low molecular weight heparins have long been the mainstay of prevention. However, parenteral administration is inconvenient for many patients, which can sometimes cause poor treatment adherence. In recent years, a new class of oral, fixed-dose anticoagulants, with different mechanisms of action, few interactions and a predictable effect, has been developed. At present, a thrombin inhibitor (dabigatran) and two FXa inhibitors (rivaroxaban and apixaban) are available for prophylaxis in patients after total knee or total hip arthroplasty. In several phase III clinical trials, these drugs have been shown to have equal or superior efficacy and a similar degree of safety to conventional therapy with enoxaparin. These new drugs can significantly improve long-term prevention, particularly in the community setting.

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Benzimidazoles; beta-Alanine; Dabigatran; Humans; Morpholines; Postoperative Complications; Pulmonary Embolism; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism

In the last few years, several phase III clinical trials of new drug treatments for deep vein thrombosis (DVT) have been carried out or are about to finish. These drugs have a predictable and reliable pharmacokinetic and pharmacodynamic response and do not require monitoring and are consequently an attractive alternative for the treatment of a high proportion of patients with DVT. Dabigatran, edoxaban and idrabiotaparinux have been developed as an alternative to warfarin, and apixaban and rivaroxaban as one-drug only treatment for this disease, with a 1- or 3-week intensified phase of initial treatment, respectively. So far, the reported results show non-inferior efficacy and safety to warfarin or to conventional treatment. Therefore, the new anticoagulants will be particularly useful in patients with unstable INRs, warfarin incompatible pharmacologic interactions, and in those without access to regular coagulation monitoring.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Biotin; Clinical Trials, Phase III as Topic; Dabigatran; Drug Administration Schedule; Humans; Morpholines; Oligosaccharides; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Venous Thrombosis

Atrial fibrillation (AF) is the most frequent supraventricular arrhythmia in our environment. The incidence and prevalence of this disease increase with age and with the presence of concomitant cardiovascular disorders; consequently, AF is frequently encountered in the field of internal medicine. Elderly patients have a series of characteristics that lead to a high risk of thromboembolic complications and hemorrhagic events. Internal medicine specialists should be trained in the global management of this disease, in order to correctly evaluate the risk of complications and take unusually difficult decisions. The new oral anticoagulants provide an interesting and promising alternative in the prevention of AF-related stroke, although there are several limitations to consider before prescribing these agents in this group of patients.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Decision Support Techniques; Humans; Internal Medicine; Morpholines; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Stroke; Thiophenes

Acute coronary syndrome (ACS) occurs as a result of atherosclerotic plaque rupture and subsequent platelet activation and coagulation leading to thrombus formation and coronary occlusion. Thrombin and activated factor X (FXa) are key elements in the coagulation cascade. The use of anticoagulants in ACS, both in the acute phase and in the long term, has improved prognosis by reducing thrombotic events, but is associated with an increased risk of bleeding. In recent years, new oral anticoagulants have been developed that do not require monitoring and produce a lower risk of bleeding. Rivaroxaban is the only drug with a favorable risk-benefit profile in patients with ACS. The ATLAS ACS TIMI 2-51 is the first phase III trial demonstrating that the addition of low-dose rivaroxaban to optimal antiplatelet therapy reduces mortality, cardiovascular mortality, infarct or stroke without significantly increasing fatal bleeding.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Azepines; Azetidines; Benzamides; Benzimidazoles; Benzylamines; beta-Alanine; Clinical Trials, Phase III as Topic; Dabigatran; Drug Administration Schedule; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes

Because of the characteristics of direct oral anticoagulants (DOA), the lack of an antidote to completely reverse their anticoagulant effects, the absence of standardization in monitoring of their effects, and limited experience of their use, specific recommendations for their management in the perioperative period or in emergencies are required. In elective surgery, in patients with normal renal function and low hemorrhagic/ thrombotic risk, DOA should be withdrawn 2 days before the intervention; when the hemorrhagic/ thrombotic risk is higher, bridge therapy with a low molecular weight hepatin beginning 5 days before the intervention is proposed as an alternative. In emergency surgery, systematic administration of hemostatic drugs as prophylaxis is not recommended. In DOA-related acute hemorrhage, administration of prothrombin complex concentrate, fresh plasma or factor VIIa should be evaluated, and general measures to control bleeding should be implemented.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Blood Loss, Surgical; Dabigatran; Humans; Morpholines; Perioperative Care; Postoperative Hemorrhage; Practice Guidelines as Topic; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism; Withholding Treatment

Non-valvular atrial fibrillation (NVAF) is the main cause of cardioembolic stroke. Classically, prevention consists of oral antivitamin-K anticoagulants (AVK), which, despite their demonstrated efficacy, continue to be underused due to their numerous drawbacks. Recently, a new generation of oral anticoagulants has been shown to have a better safety profile and greater efficacy than AVK. The studies that have compared rivoraxaban, dabigatran and apixaban with warfarin have also included a substantial proportion of patients who had previously had a stroke. The results of the substudies performed in this population with a high risk of hemorrhagic and embolic events have been consistent with those in the overall populations in these studies. The new anticoagulants are a feasible alternative to AVK in the secondary prevention of ictus in patients with NVAF. When anticoagulant therapy is contraindicated, percutaneous closure of the left atrial appendage could be an alternative.

Topics: Anticoagulants; Atrial Appendage; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Contraindications; Dabigatran; Endovascular Procedures; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Secondary Prevention; Spain; Stroke; Thiophenes

The new oral anticoagulants are now a reality and are available to clinicians. Although a large number of patients have been included in the many clinical trials of these drugs, there is one population that is always underrepresented - called special populations - such as those aged more than 75 years old, the obese, and patients with renal impairment. This review aims to analyze differences in the efficacy and safety in these special populations recruited in the various trials.

Topics: Administration, Oral; Age Factors; Anticoagulants; Benzimidazoles; Contraindications; Dabigatran; Embolism; Humans; Morpholines; Obesity; Pyrazoles; Pyridines; Pyridones; Renal Insufficiency; Rivaroxaban; Stroke; Thiophenes; Thrombosis

Venous thromboembolism (VTE) is a common and often life-threatening cardiovascular disorder. Patients undergoing total hip replacement or total knee replacement surgery are at increased risk of VTE. In this setting, clinical practice guidelines recommend the use of low molecular weight heparins, vitamin K antagonists or fondaparinux for the prevention of VTE. However, the use of these anticoagulants is beset by practical difficulties that reduce compliance to therapy and adherence to recommended guidelines. New oral anticoagulants (OACs) that are administered in fixed doses without the need for monitoring are now being introduced to clinical practice. Rivaroxaban, dabigatran and apixaban are either approved or in advanced stages of clinical development for the prevention and/or treatment of VTE. This article provides an overview of the phase III clinical development programmes for these novel OACs, with special focus on rivaroxaban. With encouraging data already emerging, the promise of a simplified single-drug approach for VTE treatment is on the horizon.

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Benzimidazoles; Clinical Trials, Phase III as Topic; Dabigatran; Humans; Medication Adherence; Morpholines; Practice Guidelines as Topic; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Thromboembolism

Direct experimental safety comparisons of Xa coagulation factor direct inhibitors, apixaban and rivaroxaban, on their approved therapeutic indications have not been identified. Due to recently raised safety concerns, a meta-analysis was carried out pooling data from studies identified on a Medline and Cochrane Library search in order to better evaluate the safety profile of both drugs. Abstracts from scientific meetings were also searched from 2003 to 2011. Primary and secondary outcome measures were major bleeding and total bleeding, respectively. Relative risks (RRs) were estimated using random effects models and statistical heterogeneity was estimated with I(2) statistics. Of the 160 screened publications, 12 clinical trials were included in which enoxaparin was the active control. For knee arthroplasty, apixaban was associated with significantly fewer major bleeding events (6496 patients, RR 0.56, 95% confidence interval [CI] 0.32-0.96) and fewer total bleeding events (6496 patients, RR 0.81, 95% CI 0.67-0.97). There were no significant differences in the incidence of major bleeding events (5699 patients, RR 1.40, 95% CI 0.56-3.52) or in the incidence of total bleeding events for rivaroxaban (5699 patients, RR 1.09, 95% CI 0.91-1.30). No differences were found when thromboprophylaxis after hip replacement was the case. Apixaban seems to be associated with a lower risk of the incidence of hemorrhagic events after total knee arthroplasty. For hip arthroplasty, no differences were found between the studied drugs.

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Humans; Morpholines; Postoperative Complications; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thrombosis

Atrial fibrillation/flutter is the most common cardiac arrhythmia that can potentially result in stroke and death. For many years, aspirin and warfarin have been the cornerstone of stroke prevention among such patients. Although warfarin therapy has been advocated for patients with high likelihood of stroke, it requires close surveillance and monitoring, has a narrow therapeutic window and is quite often affected by medication interactions and diet. Thus, the need for a better and more consistent anticoagulant therapy was necessary and has been under development with various successes for many years. This article will review 3 new antithrombotic medications that may potentially become the mainstay for treatment of patients with atrial fibrillation in the near future.

Topics: Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Fibrinolytic Agents; Humans; Morpholines; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Warfarin

Stroke is a leading cause of cardiovascular morbidity and mortality worldwide. Approximately, 795,000 strokes occur in the USA each year, 610,000 of which are first events, and 185,000 of which are recurrent events. Of all strokes, 87% are ischemic strokes. Novel anticoagulants serve as an alternative antithrombotic intervention in patients with ischemic cerebrovascular disease. This paper reviews the role of the novel anticoagulants, dabigatran, rivaroxaban and apixaban, in stroke prevention among patients with nonvalvular atrial fibrillation.

Topics: Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes

Warfarin has long been considered the gold standard for stroke prevention in patients with atrial fibrillation (AF). Recently, three major trials comparing the efficacy and safety of new drugs: a thrombin inhibitor dabigatran and two inhibitors of factor Xa - rivaroxaban and apixaban, with that of warfarin, have been published. The aim of this paper is to present the main results of the RE-LY, ROCKET AF and ARISTOTLE trials, compare study populations and outcomes, and discuss clinical implications of their results for the long-term anticoagulation in patients with nonvalvular AF.

Topics: Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Evidence-Based Medicine; Hemorrhage; Humans; Morpholines; Patient Selection; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Stroke; Thiophenes; Time Factors; Treatment Outcome; Warfarin

After more than 50 years of thrombosis treatment and prophylaxis being based on heparin and vitamin K antagonists, a new generation of oral, direct anticoagulants is now available. The past 5 years have brought a strikingly large number of trials that evaluated these new oral anticoagulants in a range of clinical trials, particularly nonvalvular atrial fibrillation, thrombosis prophylaxis after major joint replacement surgery, treatment of venous thromboembolic events, and, most recently, acute coronary syndrome. These studies have been notably similar in design between the drugs for specific indication. This review focuses on the 3 drugs that either have recently been approved by the US Food and Drug Administration (dabigatran and rivaroxaban) or have the most mature phase III clinical data (apixaban).

Topics: Acute Coronary Syndrome; Administration, Oral; Animals; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Blood Coagulation; Dabigatran; Hemorrhage; Humans; Morpholines; Orthopedic Procedures; Pyrazoles; Pyridones; Risk Assessment; Risk Factors; Rivaroxaban; Thiophenes; Thrombosis; Treatment Outcome

For more than 60 years, vitamin K antagonists have been the only available oral anticoagulants for the prevention of stroke and systemic embolism in atrial fibrillation (AF). Several new molecules, with a favorable pharmacokinetic profile and avoiding routine monitoring, have been recently developed, opening a new era in anticoagulation. The oral direct thrombin inhibitor, dabigatran, and the oral activated factor X inhibitors, rivaroxaban and apixaban, are the novel oral anticoagulants with data from large randomized clinical trials showing that these drugs are noninferior to warfarin in the prevention of stroke and thromboembolic complications of AF, with the advantage of less hemorrhagic stroke and intracranial bleeding. While these trial data are extremely encouraging, several practical issues (e.g., lack of specific antidote, safety of long-term treatment or cost-effectiveness in "real-life" clinical practice) still need to be elucidated.

Topics: Anticoagulants; Atrial Fibrillation; Drugs, Investigational; Factor X; Fibrinolytic Agents; Humans; Morpholines; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Stroke; Thiophenes; Thromboembolism; Vitamin K; Warfarin

Topics: Clinical Trials, Phase III as Topic; Factor Xa Inhibitors; Humans; Morpholines; Orthopedic Procedures; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism

Venous thromboembolism (VTE) incurs considerable socioeconomic costs, partly owing to the fact that the treatment and prevention of VTE via effective thromboprophylaxis remains suboptimal in the inpatient and outpatient settings of many healthcare systems. A number of organizations-including the National Quality Forum, The Joint Commission, and the Centers for Medicare and Medicaid Services-have established measures to assess and reduce the healthcare burden of VTE. These improvement strategies focus on increasing the use of thromboprophylaxis, implementing existing guidelines, and improving awareness.. Based on clinical trial results, the oral anti-coagulants rivaroxaban, apixaban, and dabigatran etexilate have been approved in many countries for the prevention of VTE in patients after elective hip or knee replacement surgery. Recently, dabigatran etexilate and rivaroxaban have also been approved in the US for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. In addition, rivaroxaban is currently the only newer anti-coagulant that has been approved in Europe for the treatment of deep vein thrombosis and for the long-term prevention of recurrent VTE. These oral anti-coagulants have several advantages over established anti-coagulants, including no need for routine coagulation monitoring and only minimal food and drug interactions. These characteristics, together with convenient oral administration, may improve adherence and quality of life for patients, which could result in reductions in the rate of VTE.. These three oral agents have several advantages over established anti-coagulants and could, therefore, address the unmet needs of patients, physicians, and healthcare systems, with the potential to reduce the burden of anti-coagulant management and the occurrence of VTE.

Topics: Anticoagulants; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Economics, Pharmaceutical; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism

The present systematic review was conducted to assess the efficacy and safety of apixaban versus other anticoagulants, for the prevention of venous thromboembolism (VTE) following total hip replacement (THR) and total knee replacement (TKR) surgery. Electronic databases were interrogated to identify relevant randomized controlled trials. A series of direct/indirect comparisons and a network meta-analysis were conducted. Indirect comparisons found that the odds ratio of "all VTE and all-cause death" were significantly higher for dabigatran than for apixaban in patients with THR (odds ratio [OR], 2.51; 95% confidence interval [CI], 1.50-4.21) and TKR (OR, 1.72; 95% CI, 1.22-2.42). Rivaroxaban showed similar efficacy to apixaban in patients with THR and TKR (OR, 0.69; 95% CI, 0.38-1.25 and OR, 0.83; 95% CI, 0.57-1.19, respectively). No significant differences were observed in bleeding outcomes between treatments. The novel anticoagulants apixaban, rivaroxaban, and dabigatran demonstrated similar or improved efficacy and similar safety compared with current therapies in this indication.

Topics: Antithrombins; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Benzimidazoles; beta-Alanine; Dabigatran; Female; Hemorrhage; Humans; Male; Morpholines; Postoperative Complications; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism

Venous thromboembolism (VTE) is a major public health concern since the incidence of VTE rises substantially with age. Furthermore, the diagnosis can be elusive since patients can present differently, causing delay in diagnosis and initiation of treatment and resulting in major morbidity and mortality. In addition to accuracy and precision in diagnosis, antithrombotic therapies are the cornerstones of VTE management. In traditional paradigm, vitamin K antagonists (warfarin), indirect factor Xa inhibitors, and heparin are the foundation in management of VTE. Warfarin has been the only available oral anticoagulant therapy for several decades. Although warfarin is effective in both treatment and prophylaxis against VTE, there are several limitations. Therefore, the novel anticoagulation therapies, including rivaroxaban, apixaban, and dabigatran etexilate, have apparent advantages over warfarin in terms of clinical efficacy and adverse effects. The objective of this review is to describe the background and clinical implications of these novel anticoagulants.

Topics: Acute Coronary Syndrome; Administration, Oral; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Factor Xa; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism; Vitamin K; Warfarin

Venous thromboembolism (including deep vein thrombosis and pulmonary embolism) and atrial fibrillation are common conditions in Western countries. The mainstay of treatment and prevention for these diseases is fast-acting anticoagulant drugs such as heparins and vitamin K antagonists. The use of these drugs is, however, complex and demanding for both patients and physicians. Recently, new antithrombotic drugs that act directly by inhibiting activated coagulation factors such as factor X or thrombin have been developed and investigated in phase III clinical trials. The aim of this article is to review: (i) the need to develop new drugs; (ii) their efficacy/safety as demonstrated in clinical trials; (iii) the need for laboratory monitoring and (iv) the direction towards the use of these new drugs in the real-life clinical situation.

Topics: Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Dabigatran; Drugs, Investigational; Heparin; Humans; International Normalized Ratio; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Treatment Outcome; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE) and its long-term secondary complications are major health problems associated with high rates of morbidity and mortality and considerable costs for healthcare systems. Many patients receive suboptimal therapy, despite the availability of established and effective agents (including low molecular weight heparins, unfractionated heparin, fondaparinux and vitamin K antagonists) and evidence-based, internationally recognised guidelines. Limited knowledge of guidelines, concerns about bleeding risks and the inconvenience of parenteral administration and routine coagulation monitoring contribute to non-adherence to guidelines. Newer oral anticoagulants such as rivaroxaban, dabigatran etexilate, apixaban and edoxaban, which do not have the limitations of established anticoagulants, have been developed.. Phase III randomised controlled trials for the treatment of acute VTE or for secondary prevention of recurrent VTE were identified in the PubMed and ClinicalTrials.gov databases. The search was limited to phase III studies and performed up to 26 March 2012 with the terms 'rivaroxaban OR Xarelto', 'dabigatran OR Pradaxa', 'apixaban OR Eliquis' and 'edoxaban OR DU-176b OR Lixiana'.. A total of ten phase III studies, four published (three rivaroxaban, one dabigatran), three completed with results presented at recent congresses (dabigatran), and three ongoing (two apixaban, one edoxaban) were identified. Published and completed studies showed that rivaroxaban and dabigatran provided effective and convenient short-term treatment for deep vein thrombosis and VTE, respectively, when compared with standard of care, and showed superiority for long-term prevention of recurrent VTE when compared with placebo. Currently, rivaroxaban is the only newer anticoagulant that has been approved in Europe for the treatment of deep vein thrombosis and prevention of recurrent VTE.. Based on results of completed trials, rivaroxaban and dabigatran both may reduce the incidence of secondary complications of VTE and associated socioeconomic costs. Introduction of these newer anticoagulants is likely to have a substantial impact on clinical practice.

Topics: Anticoagulants; Benzimidazoles; beta-Alanine; Clinical Trials, Phase III as Topic; Dabigatran; Follow-Up Studies; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Risk Assessment; Rivaroxaban; Thiazoles; Thiophenes; Venous Thromboembolism

New oral anticoagulants, including apixaban, dabigatran, and rivaroxaban, have been developed as alternatives to warfarin, the standard oral anticoagulation therapy for patients with atrial fibrillation (AF). A systematic review and meta-analysis of randomized controlled trials was performed to compare the efficacy and safety of new oral anticoagulants to those of warfarin in patients with AF. The published research was systematically searched for randomized controlled trials of >1 year in duration that compared new oral anticoagulants to warfarin in patients with AF. Random-effects models were used to pool efficacy and safety data across randomized controlled trials. Three studies, including 44,563 patients, were identified. Patients randomized to new oral anticoagulants had a decreased risk for all-cause stroke and systemic embolism (relative risk [RR] 0.78, 95% confidence interval [CI] 0.67 to 0.92), ischemic and unidentified stroke (RR 0.87, 95% CI 0.77 to 0.99), hemorrhagic stroke (RR 0.45, 95% CI 0.31 to 0.68), all-cause mortality (RR 0.88, 95% CI 0.82 to 0.95), and vascular mortality (RR 0.87, 95% CI 0.77 to 0.98). Randomization to a new oral anticoagulant was associated with a lower risk for intracranial bleeding (RR 0.49, 95% CI 0.36 to 0.66). Data regarding the risks for major bleeding (RR 0.88, 95% CI 0.71 to 1.09) and gastrointestinal bleeding (RR 1.25, 95% CI 0.91 to 1.72) were inconclusive. In conclusion, the new oral anticoagulants are more efficacious than warfarin for the prevention of stroke and systemic embolism in patients with AF. With a decreased risk for intracranial bleeding, they appear to have a favorable safety profile, making them promising alternatives to warfarin.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Embolism; Humans; Morpholines; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Warfarin

Novel oral anticoagulants (NOACs) have become available for different clinical indications such as the prevention of venous thromboembolism (VTE) after major orthopaedic surgery, for the treatment of VTE and stroke prevention in patients with atrial fibrillation (AF). One thrombin inhibitor (dabigatran etexilate) and two factor Xa-inhibitors (rivaroxaban and apixaban) are the most advanced NOACs and therefore, up-to-date information on their evidence and use in clinical practice appears timely. In this review we give a concise overview of the pharmacology and clinical evidence derived from phase 3 clinical trials. Then the meaningfulness of laboratory testing is discussed and recommendations are given for clinical scenarios that may necessitate adjustment of their use. We conclude that NOACs are valuable alternatives to heparins or vitamin K antagonists (VKA) in the prevention and treatment of VTE and for the prevention of stroke in patients with AF. Prescribers should however be aware of special situations and patient populations where the manufacturers' instructions need to be carefully followed. In particular, patients with comorbidities and co-medications may require individual decision making in order to prevent bleeding complications.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; Blood Coagulation; Blood Coagulation Tests; Dabigatran; Drug Monitoring; Evidence-Based Medicine; Factor Xa Inhibitors; Hemorrhage; Humans; Morpholines; Practice Guidelines as Topic; Predictive Value of Tests; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiophenes; Thrombin; Thromboembolism

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

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

The oral direct factor Xa inhibitors include rivaroxaban and apixaban that recently have been evaluated comprehensively in multiple randomized clinical trials. Based on the efficacy and safety data from these trials, these novel anticoagulants are disseminating throughout clinical practice for thromboprophylaxis in major lower-extremity joint replacement, acute medical illness, atrial fibrillation, and acute coronary syndromes. The advantages of the xabans over vitamin K antagonists include no requirement for routine anticoagulation monitoring as well as a fast and reliable onset of action. The first perioperative limitation of the xabans is the lack of a routine coagulation test for monitoring their anticoagulant effect in scenarios, such as the timing of surgical procedures, the reversal of xaban-related bleeding, and the conduct of regional anesthesia. A second perioperative limitation is the lack of fully validated clinical reversal agents although prothrombin complex concentrate, recombinant factor VIIa, and factor X concentrate are options for xaban reversal in life-threatening bleeding scenarios. Given their clinical efficacy and advantages, further xabans are in clinical development, with edoxaban already in phase III clinical trials. Although the xabans have ushered in a new paradigm for clinical anticoagulation, further clinical trials are indicated to refine their clinical indications even further, such as anticoagulation for patients with mechanical heart valves.

Topics: Acute Coronary Syndrome; Anesthesia, Conduction; Animals; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Humans; Morpholines; Perioperative Care; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism

Platelet inhibitors and anticoagulants are called antithrombotic drugs. New platelet inhibitors prasugrel and ticagrelor are more effective than the traditional clopidogrel, but their use is also accompanied by more frequent bleeding complications. Varfarin has gained true competitors; new oral anticoagulants include dabigatran, rivaroxaban and apixaban. New anticoagulants are easier to use but clearly more expensive. The use of new anticoagulants is also accompanied by several potential problems that the clinician should be aware of.

Topics: Adenosine; Anticoagulants; Benzimidazoles; beta-Alanine; Clopidogrel; Dabigatran; Hemorrhage; Humans; Morpholines; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Ticagrelor; Ticlopidine; Warfarin

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

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

The vitamin K antagonists (VKA) available for stroke prevention in patients with atrial fibrillation have many drawbacks due to their difficult clinical use and high risk of bleeding. Currently, several drugs are being developed as possible substitutes for VKA that have many advantages such as the lack of monitoring requirement and scarce pharmacologic and food interactions. The present article provides an update on the new oral anticoagulants that are in a more advanced stage of clinical research, their pharmacologic properties, advantages and disadvantages and their results in recent clinical trials.

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; beta-Alanine; Clinical Trials as Topic; Dabigatran; Drug Monitoring; Drugs, Investigational; Hemorrhage; Humans; Morpholines; Multicenter Studies as Topic; Patient Care Planning; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Thrombophilia; Vitamin K

Stroke prevention in atrial fibrillation (AF) has been challenging over decades, mostly due to a number of difficulties associated with oral vitamin K antagonists (VKAs), which have been the most effective stroke prevention treatment for a long time. The oral direct thrombin inhibitors (e.g., dabigatran) and oral direct inhibitors of factor Xa (e.g., rivaroxaban, apixaban) have emerged recently as an alternative to VKAs for stroke prevention in AF. These drugs act rapidly, and have a predictable and stable dose-related anticoagulant effect with a few clinically relevant drug-drug interactions. The novel oral anticoagulants are used in fixed doses with no need for regular laboratory monitoring of anticoagulation intensity. However, each of these drugs has distinct pharmacological properties that could influence optimal use in clinical practice. The following phase 3 randomized trials with novel oral anticoagulants versus warfarin for stroke prevention in AF have been completed: the Randomized Evaluation of Long-term Anticoagulant therapy (RE-LY) trial with dabigatran, the Rivaroxaban Once daily oral direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial with rivaroxaban, and the Apixaban for Reduction of Stroke and Other Thromboembolism Events in Atrial Fibrillation (ARISTOTLE) trial with apixaban. Moreover, the Apixaban Versus Acetylsalicylic Acid to prevent Strokes (AVERROES) trial included patients with AF who have failed or were unsuitable for warfarin, and compared apixaban versus aspirin for stroke prevention in AF. Overall, apixaban has two large trials for stroke prevention in AF showing benefits not only over warfarin, but also over aspirin among those patients who have failed or refused warfarin. In the ARISTOTLE trial, apixaban was superior to warfarin in the reduction of stroke or systemic embolism, major bleeding, intracranial hemorrhage, and all-cause mortality, with a similar reduction in the rate of ischemic stroke and better tolerability. When compared with aspirin in the AVERROES trial, apixaban was associated with more effective reduction of stroke, a similar risk of major bleeding, and better tolerability. In this review article, the authors summarize the current knowledge on novel oral anticoagulants and discuss the clinical aspects of their use for stroke prevention in AF, with particular emphasis on apixaban.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Warfarin

To analyse clinical outcomes with new oral anticoagulants for prophylaxis against venous thromboembolism after total hip or knee replacement.. Systematic review, meta-analysis, and indirect treatment comparisons.. Medline and CENTRAL (up to April 2011), clinical trials registers, conference proceedings, and websites of regulatory agencies.. Randomised controlled trials of rivaroxaban, dabigatran, or apixaban compared with enoxaparin for prophylaxis against venous thromboembolism after total hip or knee replacement. Two investigators independently extracted data. Relative risks of symptomatic venous thromboembolism, clinically relevant bleeding, deaths, and a net clinical endpoint (composite of symptomatic venous thromboembolism, major bleeding, and death) were estimated using a random effect meta-analysis. RevMan and ITC software were used for direct and indirect comparisons, respectively.. 16 trials in 38,747 patients were included. Compared with enoxaparin, the risk of symptomatic venous thromboembolism was lower with rivaroxaban (relative risk 0.48, 95% confidence interval 0.31 to 0.75) and similar with dabigatran (0.71, 0.23 to 2.12) and apixaban (0.82, 0.41 to 1.64). Compared with enoxaparin, the relative risk of clinically relevant bleeding was higher with rivaroxaban (1.25, 1.05 to 1.49), similar with dabigatran (1.12, 0.94 to 1.35), and lower with apixaban (0.82, 0.69 to 0.98). The treatments did not differ on the net clinical endpoint in direct or indirect comparisons.. A higher efficacy of new anticoagulants was generally associated with a higher bleeding tendency. The new anticoagulants did not differ significantly for efficacy and safety.

Topics: Administration, Oral; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Benzimidazoles; beta-Alanine; Dabigatran; Enoxaparin; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism

After a gap of almost 60 years following the development of warfarin, 2 new categories of oral anticoagulant agents have been approved for clinical use - the direct thrombin inhibitors and factor Xa inhibitors. These agents promise to be more convenient to administer with fixed dosing but still have equivalent efficacy and improved bleeding risk compared to warfarin. The clinical community is looking forward to the widespread usage of these agents but there is also some apprehension regarding bleeding risks, non-availability of specific reversal strategies and lack of specific monitoring parameters. This review article will attempt to educate the reader about three representative drugs from these classes: Dabigatran, Rivaroxaban and Apixaban. We will discuss the historical perspective to the development of these drugs, available research data and pharmacology of these agents. The best strategies for monitoring and reversal of these drugs in special situations will also be touched upon.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thromboembolism

Acute coronary syndromes (ACS) cause cessation of myocardial blood flow leading to coronary ischemia. The standard medical treatment includes heparin or low molecular weight heparin in the hospital, antiplatelet agents in the hospital and long term, and occasionally warfarin long term. All of these therapies are associated with bleeding complications. Furthermore, warfarin, with its narrow therapeutic window and need for frequent laboratory monitoring, poses several disadvantages. The development of novel oral factor Xa inhibitors and oral direct thrombin inhibitors may provide an alternative to warfarin. In this review, we discuss the new agents, rivaroxaban, apixaban, and dabigatran, for the potential treatment of ACS. We also review the relevant clinical trials evaluating their effects in ACS. These novel anticoagulants allow convenience of use with no requirement for laboratory monitoring and limited drug interactions, which may provide multifaceted treatment options for ACS and anticoagulation in the future.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Antithrombins; Aspirin; Benzimidazoles; beta-Alanine; Clopidogrel; Dabigatran; Drug Therapy, Combination; Factor Xa Inhibitors; Hemorrhage; Heparin; Humans; Morpholines; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Ticlopidine; Warfarin

New oral anticoagulant drugs are emerging as alternatives to warfarin for the prevention of stroke in patients with non-valvular atrial fibrillation. Two agents are direct factor Xa inhibitors (rivaroxaban and apixaban), and the third is a direct thrombin inhibitor (dabigatran). They have been separately compared to warfarin in large randomised trials. Our objective was to indirectly compare the three agents to each other for major efficacy and safety outcomes. Studies were assessed for comparability and the odds ratios of selected outcomes for each anticoagulant versus one another were estimated indirectly. The three cohorts differed significantly in terms of CHADS(2) score and the number of individuals with a past history of stroke, transient ischemic attack or systemic embolism. The estimated odds ratio of stroke or systemic embolism was 1.35 for rivaroxaban vs dabigatran 150 mg (p=0.04), 0.97 for rivaroxaban versus dabigatran 110 mg (p=0.81), 1.22 for apixaban versus dabigatran 150 mg (p=0.18), 0.88 for apixaban versus dabigatran 110 mg (p=0.34) and 0.90 for apixaban versus rivaroxaban (p=0.43). The estimated odds ratio of major bleeding was 1.10 for rivaroxaban versus dabigatran 150 mg (p=0.36), 1.28 for rivaroxaban versus dabigatran 110 mg (p=0.02), 0.74 for apixaban versus dabigatran 150 mg (p=0.004), 0.87 for apixaban versus dabigatran 110 mg (p=0.17) and 0.68 for apixaban versus rivaroxaban (p<0.001). In conclusion, the available data indicate no significant difference in efficacy between dabigatran 150 mg and apixaban for the prevention of stroke or systemic embolism in patients with non-valvular atrial fibrillation. It appears however that apixaban is associated with less major bleeding than dabigatran 150 mg or rivaroxaban and that rivaroxaban is less effective than dabigatran 150 mg in preventing stroke or systemic embolism. Such an indirect comparison should be used only to generate hypotheses which need to be tested in a dedicated randomised trial comparing the three drugs directly.

Topics: Aged; Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Clinical Trials, Phase III as Topic; Dabigatran; Embolism; Factor Xa Inhibitors; Female; Heart Valve Diseases; Hemorrhage; Humans; Ischemic Attack, Transient; Male; Morpholines; Multicenter Studies as Topic; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Secondary Prevention; Severity of Illness Index; Stroke; Thiophenes; Thrombophilia; Vitamin K; Warfarin

Vit-K antagonists are the therapy of choice to prevent thromboembolic events due to atrial fibrillation since many years. New oral anticoagulants (NOA) showed encouraging results vs. warfarin but there are no data directly comparing different NOA. We performed an adjusted indirect meta-analysis.. Randomized controlled trials (RCTs) were searched. Efficacy end points were the cumulative rate of thomboembolic stroke (TES) and systemic embolism (SE). Main safety end point was the rate of hemorrhagic stroke (HS).. Three RCTs (50578 patients) were included. Overall, NOA were comparable to warfarin according to the cumulative risk of TES and SE, as well as for TES alone. NOA were associated with a reduced rate of SE [OR 0.64 (0.44, 0.94], P=0.02]. Compared to warfarin, NOA were associated with a significantly reduced risk of HS [OR 0.43 (0.34, 0.55), P<0.001, NNT to avoid a HS 153] and all cause death [OR 0.90 [0.84, 0.96], P=0.03, NNT to save one fatality 43]. Head to head comparison showed that in terms of cumulative rate of TES/SE, as well as of TES, none of the NOA was significantly superior to the others (all Ps>0.05). Rivaroxaban showed superiority in the prevention of SE. Dabigatran 150 mg/twice daily was associated with the largest reduction in the risk of HS vs. warfarin and vs. other NOA. Overall mortality was quite comparable across NOA.. Overall superiority of NOA over warfarin is largely influenced by the reduction of HS. Dabigatran 150 mg/twice daily seems to have the best risk/benefit profile.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Biological Availability; Comparative Effectiveness Research; Dabigatran; Drug Monitoring; Embolism; Female; Humans; Male; Middle Aged; Morpholines; Outcome and Process Assessment, Health Care; Pharmacovigilance; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Risk Assessment; Rivaroxaban; Stroke; Thiophenes; Warfarin

Emergency department (ED) clinicians are not typically involved in the long-term management of patients' anticoagulation therapy, but they are responsible for decision making for emergency conditions requiring anticoagulation, such as acute venous thromboembolism (VTE). In addition, emergency physicians are often faced with patients who present first to the ED with conditions that may prompt long-term anticoagulation upon hospital discharge, such as atrial fibrillation (AF), or who have acute or potential bleeding complications from anticoagulation.. In this review, clinical trials of new oral anticoagulants evaluated for treatment of VTE and stroke prophylaxis in AF, as well as practical management aspects, will be discussed. In addition, clinical trials evaluating the adjunctive use of the new oral anticoagulants with antiplatelet therapy in patients who have experienced acute coronary syndrome will be explored.. Both dabigatran etexilate and rivaroxaban have successfully completed phase III trials for acute VTE treatment and are currently approved for the reduction of risk of stroke and systemic embolism in patients with nonvalvular AF. In a recently completed phase III trial, apixaban also demonstrated promising efficacy and safety in that indication. Rivaroxaban represents the only new anticoagulant to date to have shown promising phase III results as an adjunct to antiplatelet therapy after acute coronary syndrome.. Knowledge of the appropriate clinical use and safety concerns of the new anticoagulants is imperative as they become more frequently prescribed, and their potential uses in the ED setting represent an important aspect of continuing education for emergency physicians.

Topics: Acute Coronary Syndrome; Anticoagulants; Atrial Fibrillation; Benzimidazoles; Dabigatran; Emergency Service, Hospital; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiophenes; Venous Thromboembolism

A network meta-analysis of the three new oral anticoagulants was performed from the three trials comparing dabigatran, rivaroxaban and apixaban with warfarin in patients with atrial fibrillation.. Data were extracted of the RE-LY study of dabigatran 110 mg bid and dabigatran 150 mg bid, the ROCKET AF trial of rivaroxaban and the ARISTOTLE trial of apixaban for the composite outcome of ischemic stroke and systemic embolism, for major bleeding, intracerebral bleeding, mortality and myocardial infarction.. Dabigatran (150 mg bid) showed superior efficacy in preventing ischemic stroke plus systemic embolism to dabigatran (110 mg bid, P=0.0364) and rivaroxaban (P=0.0388). Apixaban had equivalent efficacy with rivaroxaban and dabigatran (either dose). Apixaban was safer (less major bleeding) than dabigatran (150 mg bid, P=0.036) or rivaroxaban (P=0.0002). Intracerebral hemorrhage occurred with equal frequency for all agents except for rivaroxaban (higher risk than dabigatran 110 mg bid, P=0.0070). Myocardial infarction occurred less frequently with rivaroxaban and apixaban compared to either dose of dabigatran (all P<0.05).. All-cause mortality was not different for any agent or regimen. In the absence of head-to-head comparisons, this network meta-analysis suggests that apixaban and dabigatran 110 mg bid may offer the best benefit-risk balance for stroke prevention in non-valvular atrial fibrillation. Dabigatran 150 mg bid may be preferred for patients with a high risk for embolism.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cerebral Hemorrhage; Chi-Square Distribution; Dabigatran; Embolism; Female; Humans; Male; Middle Aged; Morpholines; Myocardial Infarction; Odds Ratio; Pyrazoles; Pyridones; Risk Assessment; Risk Factors; Rivaroxaban; Stroke; Thiophenes; Treatment Outcome

In this overview we address the three phase III studies that compared new oral anticoagulants (dabigatran, rivaroxaban and apixaban) with warfarin in the setting of stroke prevention in atrial fibrillation. Strengths and weaknesses of the studies were examined in detail through indirect comparison. We analyze and comment the inclusion and exclusion criteria, the characteristics of randomized patients, the primary efficacy and safety end points and side effects. All new oral anticoagulants resulted in being non-inferior to vitamin K antagonists in reducing stroke or systemic embolism in patients with atrial fibrillation. Dabigatran 150 mg and apixaban were superior to vitamin K antagonists. Importantly, new oral anticoagulants significantly reduced hemorrhagic stroke in all three studies. Major differences among new oral anticoagulants include the way they are eliminated and side effects. Both dabigatran and apixaban were tested in low- to moderate-risk patients (mean CHADS2 [Congestive heart failure, Hypertension, Age, Diabetes, Stroke] score = 2.1-2.2) whereas rivaroxaban was tested in high-risk patients (mean CHADS2 score = 3.48) and at variance with dabigatran and apixaban was administered once daily. Apixaban significantly reduced mortality from any cause. The choice of a new oral anticoagulant should take into account these and other differences between the new drugs.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Clinical Trials, Phase III as Topic; Dabigatran; Evidence-Based Medicine; Female; Hemorrhage; Humans; Male; Middle Aged; Morpholines; Patient Safety; Preventive Health Services; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Treatment Outcome; Warfarin

Atrial fibrillation (AF), the most common cardiac arrhythmia, is associated with an increased risk of stroke and systemic embolism. Oral anticoagulation with vitamin K antagonists (VKAs), such as warfarin, has historically been the mainstay of long-term thromboprophylaxis in AF patients. However, although highly effective, VKAs have a number of limitations that make their use difficult and cumbersome in clinical practice. They have a slow onset and offset of action, narrow therapeutic window, marked dose-response variability, and multiple food and drug interactions, and require frequent coagulation monitoring and dose adjustments. To overcome VKA drawbacks, several new oral anticoagulants have been recently developed for use in AF, and three of them, the direct thrombin inhibitor dabigatran etexilate and the direct factor Xa inhibitors rivaroxaban and apixaban, have completed phase III trials. New agents have proven to be noninferior or superior to warfarin for AF-related stroke prevention, with similar or better safety profiles. These new drugs, with their predictable anticoagulant effect that allows for fixed dosing with no need for coagulation monitoring, have the potential to greatly simplify anticoagulation therapy for AF. Dabigatran etexilate and rivaroxaban are already approved in the United States and Europe for stroke prevention in nonvalvular AF, and dabigatran etexilate has entered current AF guidelines as an alternative to warfarin. However, some issues with new compounds are still unresolved, such as the lack of antidotes and standardized tests to measure drug activity. Active postmarketing monitoring surveillance of effectiveness and safety is required in the implementation of new anticoagulant therapies.

Topics: Anticoagulants; Atrial Fibrillation; Benzimidazoles; Benzoates; Clinical Trials as Topic; Coumarins; Dabigatran; Factor Xa; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Thrombin; Warfarin

Atrial fibrillation (AF) increases the risk of stroke. New anticoagulation agents have recently provided alternative and promising approaches. This paper reviews the current state of anticoagulation therapy in AF patients, focusing on various clinical scenarios and on comparisons, where possible, between western and eastern populations.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cardiology; Dabigatran; Female; Humans; Male; Middle Aged; Morpholines; Pyrazoles; Pyridones; Risk; Risk Factors; Rivaroxaban; Stroke; Thiophenes; Warfarin

In patients with atrial fibrillation (AF) warfarin has been the mainstay therapy for stroke prevention. In recent randomized clinical trials (RCTs) oral direct thrombin inhibitor (Dabigatran) and factor Xa inhibitors (Rivaroxaban and Apixaban) challenged the efficacy and safety benchmarks set by warfarin. These drugs boast a rapid onset of action, shorter half-life and fewer drug and dietary interactions. Moreover, these new anticoagulants do not require monitoring, titration or dose adjustments. These agents have already been approved for prevention of stroke or systemic embolism in patients with AF. Uncertainty regarding suitability, efficacy and safety in certain patient subsets and issues related to the ability effectively monitor the pharmacodynamic effects and reverse the therapeutic effects of these drugs should be addressed as we engage in a widespread use of these agents in various patient subsets.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Treatment Outcome; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Decision Support Techniques; Health Status Indicators; Hemorrhage; Humans; Morpholines; Practice Guidelines as Topic; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Stroke; Thiophenes; Warfarin

Thromboembolic disorders are leading causes of morbidity and mortality, with treatment and prophylaxis a priority. There has been a heavy dependency upon warfarin and heparin for anticoagulation for 60 years. This is likely to change with the emergence of novel oral anticoagulants.. Interventional radiologists are increasingly encountering these medications, and a thorough knowledge of them is essential for appropriate periprocedural management. This article will review these novel agents, their uses, and their pharmacologic profiles and will propose guidelines for periprocedural management.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Blood Coagulation; Dabigatran; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridones; Radiography, Interventional; Rivaroxaban; Thiophenes; Thromboembolism

Atrial fibrillation (AF) is the commonest cardiac rhythm disorder worldwide, affecting 1% of the general population. It is estimated that up to 16 million people in the US will suffer from the arrhythmia by 2050. AF is an independent stroke risk factor and associated with more severe strokes. For six decades, warfarin has been the only truly effective therapy to protect against stroke for patients with atrial fibrillation. Despite the proven worth of warfarin, its limitations have seen reluctance amongst physicians and patients to utilise this efficacious agent. This has meant that substantial numbers of patients are either unprotected against stroke or suboptimally protected with antiplatelet therapy. Contemporary well-validated stroke risk factor schemes (CHA(2)DS(2)-VASc) now permit rapid but comprehensive evaluation of a patient's risk for thromboembolism, allowing better identification of low-risk patients who do not require antithrombotic therapy, and whilst for those with ≥1 stroke risk factors require formal oral anticoagulation. Aspirin has been proven to be inferior to anticoagulation, and is not free of bleeding risk. We also have simple scores to easily evaluate a patient's risk of haemorrhage (e.g. HAS-BLED). The emergence of new oral anticoagulants should further improve stroke prevention in AF, and they successfully negotiate many of the hurdles to oral anticoagulation generated by warfarin's limitations. Monitoring, reversal, and perioperative management are areas which require further investigation to enhance our ability to safely and effectively utilise the new agents.

Topics: Administration, Oral; Amiodarone; Anti-Arrhythmia Agents; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Clinical Trials, Phase III as Topic; Dabigatran; Dronedarone; Drug Design; Humans; Morpholines; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Stroke; Thiophenes; Treatment Outcome; Warfarin

For many decades Vitamin K antagonists were the standard orally given medication for primary and secondary prevention of thromboembolism in patients with atrial fibrillation and stroke. Three compounds, dabigatran, rivaroxaban, and apixaban, are now challenging this well established prescription, as they showed similar effect in preventing thromboembolism with a lower bleeding rate in recently published well designed, controlled randomised, non-inferiority trials. Their advantages of each are to have a fixed dosage, no need to monitor coagulation factors, and fewer interactions with food and other drug intake. The therapeutic effect is estimated overall similar between the three compounds. Who is a candidate for one of the new drugs: Patients with atrial fibrillation and the clear indication to get a future oral anticoagulation are potential candidates to receive one of the new drugs. Further this may be patients where the treatment with Vit K antagonists was difficult to optimise, patients who are not willing to have blood controls done regularly or where blood controls are difficult to obtain. This will also be an option in patients who had a stroke due to atrial fibrillation and had no history of cerebral bleeding. Who should not receive the new anticoagulants: patients who present stable blood coagulation values in the treatment range and no complications should not be merged to the new drugs. Patients with severe renal insufficiency or receiving a medication that interacts with the new drugs (e. g. ketoconazole) or with synthetic heart valves will not be candidates to receive the new drugs.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Humans; International Normalized Ratio; Morpholines; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Secondary Prevention; Stroke; Thiophenes; Thromboembolism; Vitamin K

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

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is a potent risk factor for stroke and transient ischemic attack. Most patients with AF receive antithrombotic stroke prophylaxis, often in the form of a vitamin K antagonist, typically warfarin. Drug treatment with warfarin is associated with significant management issues, such as an unpredictable dose response necessitating dose adjustments, frequent laboratory monitoring, and multiple interactions with other medications, as well as foods. A new generation of novel anticoagulants has emerged that includes dabigatran etexilate, a direct thrombin inhibitor, and rivaroxaban and apixaban, both highly selective factor Xa inhibitors. These newer agents possess a highly predictable pharmacokinetic-pharmacodynamic relationship, allowing for fixed dosing and no necessity for routine laboratory monitoring; additionally these agents have minimal drug interactions. Dabigatran etexilate and apixaban are both twice-daily medications, whereas rivaroxaban is administered once daily for stroke prophylaxis. The impact of dosing frequency on medication adherence with these agents has not been prospectively evaluated; however, the frequency of dosing intervals has been shown to affect medication adherence, which in turn may influence patient outcomes.

Topics: Administration, Oral; Animals; Anticoagulants; Atrial Fibrillation; Benzimidazoles; Dabigatran; Drug Administration Schedule; Humans; Medication Adherence; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiophenes; Warfarin

The standard effective treatment of venous and arterial thromboembolism includes unfractionated and low-molecular weight heparin as well as warfarin, which have major disadvantages. In recent years, new anticoagulants have been developed in an attempt to overcome the known limitations of established treatment and develop improved therapies. This chapter reviews pharmacological properties of the new anticoagulants, the most recent trials assessing their safety and efficacy as well as potential advantages and disadvantages of using these novel drugs in real life.

Topics: Anticoagulants; Antithrombins; Azetidines; Benzimidazoles; Benzylamines; Clinical Trials, Phase III as Topic; Dabigatran; Factor Xa Inhibitors; Heparin, Low-Molecular-Weight; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Thrombin; Thromboembolism; Warfarin

Recent randomized controlled trials have shown that new oral anticoagulants (dabigatran, rivaroxaban en apixaban) in patients with atrial fibrillation are equally or more effective in preventing cerebral infarction than vitamin K antagonists (VKA). New oral anticoagulants cause significant less intracranial haemorrhages. These results also apply to patients at high risk for complications such as those with a history of cerebral infarction, and those aged 75 years and over. It is not known whether patients in the acute phase after cerebral infarction and those with blood pressure exceeding 180/110 mmHg benefit as well. Monitoring anticoagulation is no longer needed in patients using these new oral anticoagulants, which makes daily use easier but provides less insight into medication compliance. There is no need to switch medication in patients who respond well to VKA. However, new oral anticoagulants should be considered in patients who have problems with VKA and who have a de novo indication for anticoagulation. Practical issues such as interaction with other drugs, medication compliance, antagonizing, monitoring of the anticoagulation and asymptomatic deteriorating renal function should be studied further.

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

New oral anticoagulant (NOAC) regimens [dabigatran 150 mg (D150) and 220 mg (D220), rivaroxaban 10 mg (R20), and apixaban 2.5 mg bid (A5)] were effective and safe compared to enoxaparin for the prevention of venous thromboembolism (VTE) following elective total knee (TKR) or hip replacement (THR) surgery. First a cluster analysis was used to identify homogeneous studies for the trial programs of each NOAC. Second, only studies reporting VTE and VTE-related death, major bleeding, and mortality were included. The odds ratio (OR) and 95% confidence interval (CI) were calculated for each NOAC regimen versus the comparator. Third, these data were used for the indirect comparison between NOACs. Cluster analysis identified duration of treatment (10 ± 5 and 34 ± 5 days) as the only homogeneous parameter across all NOAC programs (p>0.05) except for A5 and VTE over 10 ± 5 days (analysis not performed). The results of the calculated OR and 95% CI of the four NOAC regimens over 10 ± 5 and 34 ± 5 days showed inferiority of D150 and D220 compared to R10 for VTE (p<0.01, p<0.001). Comparisons of major bleeding and mortality were not different for all indirect comparisons. Despite the lack of standard definitions for VTE and bleeding outcomes, cluster analysis seems to be an appropriate tool to identify homogeneity across trial programs and to perform an indirect comparison for NOACs for prevention of VTE following TKR and THR surgery.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Endpoint Determination; Enoxaparin; Factor Xa Inhibitors; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism

The incidence and prevalence of atrial fibrillation are quickly increasing, mainly due to the ageing of the population. Atrial fibrillation is, to date, a problem of public health. Atrial fibrillation is associated to a five-fold risk of stroke, which may be identified by score risks, such as CHADS(2) score. The classical antithrombotic treatment of atrial fibrillation is based on vitamin K antagonists. Trials made in the 90's have clearly shown that vitamin K antagonists were able to decrease stroke risk by about 60%. New oral anticoagulants are now available on the market to treat patients with atrial fibrillation. These drugs are dabigatran which has demonstrated an interest in the RE-LY trial. Two doses may be prescribed, 110 mg bid and 150 mg bid. Anti Xa have also demonstrated an interest : rivaroxaban in the ROCKET AF trial and apixaban in the AVERROES (versus aspirin) and ARISTOTLE trials. In the future these drugs will have a major place in the armamentarium used to treat patients with atrial fibrillation. In all these trials a decrease in intra cranial haemorrhages has been demonstrated. In the everyday practice it will be necessary to be very cautious in patients with impaired renal function, as all these drugs are eliminated by kidneys.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Humans; Kidney; Morpholines; Pyrazoles; Pyridones; Risk Assessment; Risk Factors; Rivaroxaban; Stroke; Thiophenes; Treatment Outcome; Vitamin K

New oral anticoagulants are ready to enter the scene on a massive basis for the treatment/prophylaxis of many cardiovascular diseases. Although they can be prescribed without dose-adjustment based on laboratory testing, the laboratory is still an essential partner that may assist clinicians for the management of anticoagulated patients. In principle, there are many tests that can be used to evaluate the anticoagulant effect of the new drugs, but the choice should be made among those that are more readily available in emergency and that are easy to run. Linearity of dose-response and responsiveness to increasing dose in addition to standardization are other important issues to consider. This article is aimed at reviewing the current tests, their characteristics and the most appropriate choice.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Blood Coagulation; Blood Coagulation Tests; Dabigatran; Dose-Response Relationship, Drug; Drug Monitoring; Hemorrhage; Humans; Morpholines; Predictive Value of Tests; Pyrazoles; Pyridones; Risk Assessment; Risk Factors; Rivaroxaban; Thiophenes

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

New oral anticoagulants promise to overcome essential drawbacks of traditional substances. They have a predictable therapeutic effect, a wide therapeutic window, only limited interaction with food and drugs and can be administered p.o. with a fixed dose. On the other hand, knowledge on the laboratory management of new anticoagulants is limited. In the present article we discuss possible indications and available assays for monitoring of Rivaroxaban, Apixaban and Dabigatran. Furthermore, we discuss interpretation of routine coagulation tests during therapy with these new drugs.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Blood Coagulation; Blood Coagulation Tests; Dabigatran; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Food-Drug Interactions; Hemostasis; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Switzerland; Thiophenes; Thromboembolism

New oral anticoagulants such as the factor Xa inhibitors rivaroxaban and apixaban or the thrombin inhibitor dabigatran lack some of the limitations of the well-known vitamin K-antagonists. Although routine monitoring is not required, large variations in overall exposure can be seen under certain circumstances. Dabigatran is primarily eliminated in unchanged form in the urine and dose has to be adapted according to renal function. The factor Xa inhibitors are CYP3A4-substrates and combination with potent CYP3A4-inhibitors is not allowed. In cases of bleeding or thromboembolic events under treatment, targeted monitoring of drug concentration or anti-FXa- or anti-FIIa-activity may be helpful to identify the underlying cause. In contrast to vitamin K antagonists or heparin, no antidotes are available for the new anticoagulants and the optimal procedure in cases of life-threatening bleeding has not yet been defined. For certain indications such as prophylaxis of venous thromboembolism in acutely ill medical patients study data are (not yet) available. Concerning localization of bleeding sites the new compounds may display a different profile compared to vitamin K-antagonists (less intracranial bleedings). Experience with long-term use (> 5 years) is limited. Therefore careful clinical monitoring of patients considering co-medication and co-morbidity is necessary to allow safe therapy with the new oral anticoagulants.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Dabigatran; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Factor Xa Inhibitors; Hemorrhage; Humans; Metabolic Clearance Rate; Morpholines; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Thiophenes; Thromboembolism; Vitamin K

Venous thromboembolism (VTE) represents one of the most preventable complications that occur during hospitalization, and measurement of hospital-associated VTE is becoming a key component in hospital quality measures. Guidelines for the prevention of deep vein thrombosis and pulmonary embolism have been published by several organizations to guide quality of care; however, some of the guidelines are divergent in their recommendations. This disagreement among guidelines is most pronounced in patients undergoing major orthopedic surgery. The advent of newer anticoagulants, which are now approved or in late-phase development, have already had an effect on the guidelines and may also affect quality measures in the future. In this article, we review the burden of VTE in patients undergoing major orthopedic surgery, highlight the differences in the guidelines, and examine the new anticoagulants as they are related to VTE prophylaxis in this patient group.

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Evidence-Based Medicine; Humans; Morpholines; Practice Guidelines as Topic; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Societies, Medical; Thiazoles; Thiophenes; Venous Thromboembolism

Topics: Aged; Anticoagulants; Atrial Appendage; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cross-Sectional Studies; Dabigatran; Humans; International Normalized Ratio; Minimally Invasive Surgical Procedures; Morpholines; Population Dynamics; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Risk Factors; Rivaroxaban; Stroke; Thiophenes

There is a high prevalence of atrial fibrillation in the United States, particularly in the elderly population. Patients with atrial fibrillation are at an increased risk of stroke and anticoagulant therapy is recommended. However, many eligible patients are not receiving therapy due to limitations and concerns related to the use of the vitamin K antagonist warfarin, such as slow onset of action, variable drug metabolism, risk of bleeding, and requirement for monitoring. Novel oral anticoagulants (NOACs) have been developed and may be used as an alternative to warfarin. This review article summarizes the current clinical trial data for warfarin compared with the NOACs dabigatran (direct thrombin inhibitor), and rivaroxaban and apixaban (factor Xa inhibitors). Dabigatran (150 mg twice daily) demonstrated superiority in reducing the stroke or systemic embolism rate compared with warfarin (1.53% vs 1.69%; P < 0.001). The risk of major bleeding was similar for dabigatran and warfarin (3.32% per year vs 3.57% per year; P = 0.32). Rivaroxaban (20 mg once daily) demonstrated noninferiority in reducing the stroke or systemic embolism rate compared with warfarin (2.1% vs 2.4%; P < 0.001). There was no significant difference between rivaroxaban and warfarin for the risk of major bleeding and clinically relevant nonmajor bleeding (14.9% per year vs 14.5% per year; P = 0.44). Apixaban (5 mg twice daily) demonstrated superiority compared with warfarin in preventing stroke or systemic embolism (1.27% vs 1.60%; P = 0.01). Apixaban significantly reduced major bleeding compared with warfarin (2.13% per year vs 3.09% per year; P < 0.001). Compared with warfarin, all-cause mortality was numerically lower for dabigatran (P = 0.051) and similar for rivaroxaban (P = 0.15). Apixaban demonstrated significantly lower mortality rates compared with warfarin (3.52% vs 3.94%; P = 0.047). All 3 NOACS--dabigatran, rivaroxaban, and apixaban--significantly reduced intracranial hemorrhage compared with warfarin. Novel oral anticoagulants may be a suitable alternative to warfarin for different patient populations due to minimal drug interactions, lower bleeding risk, and no monitoring requirement.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Humans; Morpholines; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Warfarin

Venous thromboembolic disease, including deep vein thrombosis and pulmonary embolism, is a cause of significant mortality and morbidity. For several decades, anticoagulant options for the treatment and prevention of thrombosis have been limited mainly to agents such as unfractionated heparin and oral vitamin K antagonists, such as warfarin. Although these therapies have proven benefits, they also have important limitations that result in their underuse in routine clinical practice. A variety of novel anticoagulants with improved pharmacologic and clinical profiles are in development, offering benefits over traditional therapies. Specifically, progress has been made in the development of small molecule factor Xa inhibitors and thrombin inhibitors. With their potentially consistent and predictable clinical profile, oral formulation, and decreased need for coagulation monitoring, these new agents will likely increase the use and duration of anticoagulation treatment in thromboembolic disorders and reduce the burden associated with long-term management.

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; Dabigatran; Drug Approval; Humans; Morpholines; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; United States; Venous Thrombosis

Topics: Acute Coronary Syndrome; Anticoagulants; Antithrombins; Cyclic N-Oxides; Fondaparinux; Hirudins; Humans; Morpholines; Peptide Fragments; Polysaccharides; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiophenes

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

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

As coronary artery disease (CAD) remains a leading cause of death in the world, the development of anti-coagulants to prevent CAD progressing to myocardial infarction and death is a high priority. A number of direct Factor Xa (FXa) inhibitors are being developed for use in CAD. Despite being developed to the stage of Phase II clinical trials, DX-9065a is no longer a priority with its developing company for further development, possibly because the Phase II trials did not show any major benefit of DX-9065a over heparin in subjects undergoing percutaneous coronary interventions (PCI) or with non-ST-elevation acute coronary syndromes (ACS). ZK-807834, otamixaban, apixaban, and rivaroxaban are all direct FXa inhibitors that have undergone preclinical and some clinical testing for use in CAD. In a large Phase II clinical trial of subjects with ACS, some doses of otamixaban had a better benefit/risk profile than the unfractionated heparin/eptifibatide combination. However, neither ZK-807834 nor otamixaban appear to be undergoing further clinical development at present. In ACS, placebo-controlled large Phase II clinical trials with apixaban and rivaroxaban have not shown clear cut benefits. Nevertheless, apixaban and rivaroxaban are presently in placebo-controlled Phase III clinical trials for ACS. Presently, there is no compelling evidence to support the use of direct FXa inhibitors in ACS.

Topics: Amidines; Coronary Artery Disease; Cyclic N-Oxides; Factor Xa; Factor Xa Inhibitors; Humans; Morpholines; Naphthalenes; Propionates; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes

Vitamin K antagonists (VKAs) are the main therapeutic agents used to prevent embolic events in patients with atrial fibrillation (AF). Despite their proven efficacy, VKAs are underused and have several limitations. In recent years, there has been great interest in the development of new oral anticoagulants with a more efficient pharmacological profile, first tested in venous thromboembolism prevention and later in AF.. The authors review the pharmacological differences between dabigatran, rivaroxaban and apixaban, and potential subgroups of patients in whom these new drugs would constitute a possible alternative to VKA therapy. Pharmacodynamic and pharmacokinetic data from each compound are analyzed in respect to their potential use in AF. This article provides an exhaustive review of the current status of this topic and the controversies still regarding each drug.. Apixaban and rivaroxaban are under evaluation for thromboembolic prevention in AF; dabigatran was recently approved for this indication. Therefore, it is important to know the characteristics of these drugs as a potential alternative to VKAs.

Topics: Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Drug Design; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thromboembolism; Vitamin K

A number of new oral anticoagulant drugs that selectively and directly inhibit factor Xa (FXa) appear as promising alternatives to the existing anticoagulant agents. These compounds present a convenient route of administration with predictable pharmacokinetics and pharmacodynamics that allow fixed dosing regimens without requiring coagulation monitoring. Rivaroxaban is the first of this new class of drugs that was approved for the prevention of venous thromboembolism (VTE) after elective total hip replacement or total knee replacement surgery in the EU, Canada and several other countries. Clinical trials with rivaroxaban in patients with acute VTE and in patients with atrial fibrillation have been recently completed. Numerous other compounds are under different developing stages (apixaban, edoxaban, otamixaban, LY517717, PRT-054021, YM150).. This review provides an overview of the two oral anti-FXa drugs at the most advanced stage of development (rivaroxaban and apixaban) and briefly describes and comments on the results of the most important studies.. Undoubtedly, these new drugs will offer several advantages over the previous compounds, but a number of issues still require some attention during the phase of translation from clinical trials into daily clinical practice.

Topics: Acute Coronary Syndrome; Anticoagulants; Atrial Fibrillation; Clinical Trials, Phase III as Topic; Drugs, Investigational; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Thrombosis; Venous Thromboembolism

The marketing of new anticoagulant drugs has led us to review the development of rivaroxaban and apixaban (oral anti-Xa drugs) and dabigatran (an oral thrombin inhibitor). The results are different in terms of efficacy and tolerance. Each molecule has its own field of application but it is not at all certain that each will find its place. Though the results are favourable for these orally active drugs in the orthopaedic setting, it is clear that only cardiological applications will give a final green light for these products. The future will be fascinating in this regard.

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Biological Availability; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Morpholines; Postoperative Complications; Prothrombin; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism

Anticoagulation for the long-term treatment and prevention of thrombo-embolic diseases as well as for stroke prevention in atrial fibrillation (AF) has been accomplished by vitamin K antagonists for the last half century. Although effective under optimal conditions, the imminent risk of a recurrent event vs. the risk of bleeding due to the narrow therapeutic window, numerous food- and drug interactions, and the need for regular monitoring complicate the long-term use of these drugs and render treatment with these agents complicated. As a result, novel anticoagulants which selectively block key factors in the coagulation cascade are being developed. The efficacy and safety of the direct thrombin inhibitor dabigatran etexilate, as well as of the selective factor Xa inhibitors rivaroxaban and apixaban, have been demonstrated in Phase III trials for stroke prevention in AF and the treatment and secondary prophylaxis of venous thrombo-embolism. This review summarizes the results from recently published pivotal clinical trials and discusses the opportunities as well as uncertainties in the clinical applications of these novel agents.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; Cost-Benefit Analysis; Dabigatran; Drug Approval; Factor X; Humans; Morpholines; Off-Label Use; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Venous Thromboembolism

In total hip or total knee arthroplasty, hypercoagulability typically begins on the operating table and a hypercoagulable state persists for up to 3 months after surgery. For that reason, it is critical to begin anticoagulation as soon as possible after wound closure and to continue it beyond the standard time of hospital discharge: current guidelines recommend up to 35 days following total hip arthroplasty and at least 10 days following total knee arthroplasty. Currently, low molecular weight heparin is commonly used for in-hospital prophylaxis, while for post-discharge use, warfarin is the drug most frequently prescribed in the United States. While both are efficacious, both have challenges associated with administration and, in the case of warfarin, a narrow therapeutic window, both food and drug interactions, routine blood monitoring, and an unpredictable dose response. New oral anticoagulants are being developed that will be easier to administer, have minimal or no drug interactions, and do not require coagulation monitoring. These drugs, which include dabigatran, apixaban, and rivaroxaban, should encourage improved compliance with guideline recommendations for optimal duration of thromboprophylaxis and lead to a reduced incidence of venous thrombolic events.

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Benzimidazoles; beta-Alanine; Dabigatran; Guideline Adherence; Heparin, Low-Molecular-Weight; Humans; Morpholines; Outpatients; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Time Factors; Venous Thromboembolism; Warfarin

For years, prevention and treatment of thromboembolic events have been restricted to the use of heparins and vitamin K antagonists. These treatments, in spite of their unquestioned efficacy, present numerous limits (hemorrhagic risk, need for regular laboratory controls). These limits call for the development of new antithrombotic drugs. This review briefly reports on three new molecules, in very advanced phases of clinical research: dabigatran (Pradaxa®), rivaroxaban (Xarelto®) and apixaban. These molecules represent new oral anticoagulants, which directly inhibit a coagulation factor (thrombin for dabigatran, factor Xa for rivaroxaban and apixaban) and do not need regular anticoagulant monitoring or dose adjustment. The approval is still restricted in France to the prophylaxis of venous thromboembolism in orthopaedics. Dabigratran will be soon available in the prevention of stroke in atrial fibrillation. With the forthcoming phase III studies to prevent and treat venous thromboembolism, anticoagulant therapy management will be most probably improved in the coming years.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Drug Approval; Drug Monitoring; Factor Xa Inhibitors; Fibrinolytic Agents; Forecasting; France; Humans; Morpholines; Orthopedic Procedures; Postoperative Complications; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Thrombin; Thromboembolism; Thrombophilia; Venous Thromboembolism

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Enoxaparin; Humans; Morpholines; Orthopedic Procedures; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Risk Factors; Rivaroxaban; Thiophenes; Venous Thromboembolism

Goal of this article is to select three molecules from all the candidates currently under clincial development and to present and comapre their characteristics. Dabigatran is a direct thrombin (FIIa) inhibitor, whereas Rivaroxaban and Apixaban are direct factor Xa (FXa) inhibitors. All three represent small molecules thatreversibly, rapidly and directly bind to their target, the active center of the respective activated coagulation factor. Phase III data have been published for venous thromboembolism prophylaxis for each of these three drugs. Interestingly, VTE prophylaxis is initiated postoperatively with these products. Rivaroxaban currently holds the only accepted indication in Switzerland. For the indications VTE, atrial fibrillation and acute coronary syndrome promising phase III data have been or are in the process of being published. Monitoring is not necessary for any of these three new anticoagulants.

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Biological Availability; Clinical Trials, Phase III as Topic; Dabigatran; Dose-Response Relationship, Drug; Drug Administration Schedule; Evidence-Based Medicine; Factor Xa Inhibitors; General Practice; Humans; Metabolic Clearance Rate; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism

The prevalence of obesity has increased substantially over recent years. Clinicians are increasingly being challenged with making uncertain anticoagulant dosing decisions, as the optimal dosing strategy for most anticoagulants in the obese patient population remains unknown. Research published to date suggests that the clearance of anticoagulants increases with weight. As obesity is associated with an increased risk of venous thromboembolism and arterial disease, there is an urgent need to establish appropriate anticoagulation regimens for this patient group. Research studies applying the method of pharmacokinetic-pharmacodynamic modelling and simulation could establish an appropriate evidence base and provide direction and reassurance to prescribing clinicians.

Topics: Acute Coronary Syndrome; Anticoagulants; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Double-Blind Method; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Heparin; Humans; Morpholines; Multicenter Studies as Topic; Obesity; Polysaccharides; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiophenes; Thrombin; Thrombophilia; Venous Thrombosis; Warfarin

Warfarin has been the effective treatment in the prophylaxis of cardioembolism, in particular in patients with atrial fibrillation, for more than 50 years. Nevertheless, many patients with atrial fibrillation are not currently treated because of the numerous limits of oral anticoagulation and in those treated the quality of anticoagulation is often poor. Novel oral anticoagulant drugs, the direct thrombin antagonist dabigatran and factor Xa inhibitors such as rivaroxaban, apixaban, edoxaban, and betrixaban are more predictable and convenient anticoagulants in comparison with warfarin, mainly because of the non-requirement of regular laboratory monitoring and dose adjustments. Current data from phase III clinical trials are available for dabigatran, rivaroxaban and apixaban, which show to be at least noninferior in efficacy to warfarin for the prevention of stroke in patients with atrial fibrillation. This review focuses on the potential of novel anticoagulants to replace warfarin in patients with atrial fibrillation. Also the place in therapy and the potential limitations of the new agents in clinical practice represent important issues to be considered. The promise of new oral anticoagulants gives us the hope that warfarin will finally be replaced in a near future, but more importantly that anticoagulant undertreatment of atrial fibrillation will be partially overcome.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzamides; Benzimidazoles; beta-Alanine; Clinical Trials, Phase III as Topic; Dabigatran; Evidence-Based Medicine; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Rivaroxaban; Thiazoles; Thiophenes; Thromboembolism; Treatment Outcome; Warfarin

Topics: Anticoagulants; Arthroplasty, Replacement, Knee; Benzimidazoles; beta-Alanine; Dabigatran; Factor Xa Inhibitors; Heparin; Heparin, Low-Molecular-Weight; Humans; Intermittent Pneumatic Compression Devices; Morpholines; Neurosurgical Procedures; Orthopedic Procedures; Postoperative Complications; Pulmonary Embolism; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Stockings, Compression; Surgical Procedures, Operative; Thiophenes; Urologic Surgical Procedures; Venous Thrombosis

Outpatient use of anticoagulants to prevent venous thromboembolism after total hip or knee arthroplasty may be hampered either by requirements for parenteral administration or high variability and frequent monitoring of anticoagulant activity. Trials of the new oral direct factor Xa inhibitors rivaroxaban and apixaban and the direct thrombin inhibitor dabigatran indicate that they can be administered in fixed doses without monitoring and that they generally have efficacy at least equivalent to enoxaparin, although with potential minor differences in the balance of efficacy vs risk for bleeding. This article reviews the results and pharmacokinetic properties that may influence their use in clinical practice.

Topics: Administration, Oral; Anticoagulants; Arthroplasty, Replacement; Benzimidazoles; beta-Alanine; Clinical Trials, Phase III as Topic; Dabigatran; Enoxaparin; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Treatment Outcome; Venous Thromboembolism

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Comorbidity; Dabigatran; General Practice; Humans; International Normalized Ratio; Medication Adherence; Morpholines; Partial Thromboplastin Time; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Stroke; Thiophenes

Vitamin K antagonists and heparins have been standard anticoagulation drugs over the past decades. They are effective and safe but they have several drawbacks which has led to the development of new oral anticoagulants. Dabigatran etexilate is a specific oral thrombin inhibitor and rivaroxaban and apixaban are oral inhibitors of factor Xa. These agents produce a predictable anticoagulant response after fixed-dose administration so that routine coagulation monitoring is unnecessary. Currently, dabigatran etexilate, rivaroxaban and apixaban are licensed for thromboprophylaxis after elective total hip or knee replacement surgery. Since august 2011, dabigatran etexilate is licensed for patients with atrial fibrillation, rivaroxaban will follow. However, indications will be expanded e.g. for therapy of venous thromboembolism. It is important to be aware of the pharmacokinetic and pharmacodynamic profiles of these new agents. The drugs considerably influence the global test of coagulation thus making an interpretation of test results difficult. Currently, there is a lack of suitable coagulation tests to monitor anticoagulation in emergency cases, such as bleeding. Specific antidotes are not yet available.

Topics: Administration, Oral; Antithrombins; Arthroplasty, Replacement, Hip; Atrial Fibrillation; Benzimidazoles; Blood Coagulation Tests; Critical Care; Dabigatran; Drug Approval; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Heparin; Humans; Morpholines; Postoperative Complications; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Thrombophilia; Vitamin K

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

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

The search for an oral anticoagulant with acceptable efficacy and safety in the treatment and prevention of venous and arterial thromboembolism, but with practical advantages over warfarin, has been a focus of drug development for many years. Three oral agents, dabigatran, rivaroxaban, and apixaban, are nearing approval in the US. Their use in practice will be guided by the clinical trials available, as well as their pharmacokinetic and pharmacodynamic properties. Practitioners need to be fully aware of these characteristics in order to use these agents appropriately in clinical practice. This review compares the results of the phase 3 trials investigating these agents in the prevention of venous thromboembolism in patients undergoing orthopedic surgery, examines the reporting of bleeding complications in the trials, and highlights various practical considerations regarding their use in clinical practice.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; Clinical Trials, Phase III as Topic; Dabigatran; Drugs, Investigational; Evidence-Based Medicine; Humans; Morpholines; Orthopedic Procedures; Practice Guidelines as Topic; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism

Therapeutic oral anticoagulation is still commonly achieved by administration of warfarin or other vitamin K antagonists that are associated with an untoward pharmacokinetic / pharmacodynamic (PK/PD) profile leading to a high incidence of bleeding complications or therapeutic failure. Hence, there is an unmet medical need of novel easy-to-use oral anticoagulants with improved efficacy and safety. Recent developments include the identification of non-peptidic small-molecules that selectively inhibit certain serine proteases within the coagulation cascade. Of these, the thrombin inhibitor dabigatran and factor Xa inhibitor rivaroxaban have recently been licensed for thromboprophylaxis after orthopaedic surgery mainly in Europe. In addition, the factor Xa inhibitor apixaban is in late-stage clinical development. Each drug is prescribed at fixed doses without the need of anticoagulant monitoring. Phase III trials in orthopaedic patients essentially resulted in non-inferior efficacy of dabigatran and superior efficacy of rivaroxaban over enoxaparin without any marked differences of drug safety, while apixaban data is still controversial. However, alterations of rivaroxaban and apixaban pharmacokinetics upon interactions with inhibitors and inducers of CYP3A4 or P-glycoprotein may complicate the use of these compounds in daily practice, whereas dabigatran elimination largely depends on renal function. Hence, this review reports PK/PD, efficacy and safety data of dabigatran, rivaroxaban and apixaban throughout preclinical and clinical development.

Topics: Anticoagulants; Benzimidazoles; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Treatment Outcome

Heparin, low molecular weight heparin (LMWH) and warfarin are well-established anticoagulants still in widespread use despite their well known drawbacks. Heparin requires continuous monitoring, has serious side-effects such as haemorrhage, thrombosis and osteoporosis, and lacks an oral route of administration. LMWH is a safer, more convenient anticoagulant to use but it cannot be given orally, does not have an antidote and may be difficult to administer in patients with renal failure. Warfarin has a narrow therapeutic window, interacts with other drugs and foods and requires monitoring like heparin. The limitations of all three of these established anticoagulants have prompted the search for better more convenient agents. The major examples of these newer anticoagulants are the direct and indirect factor Xa inhibitors and the direct thrombin inhibitors. These new agents tend to have more predictable pharmacokinetic properties, superior efficacy and safety and some can be administered orally. In this review, we summarise the advantages and disadvantages of three established anticoagulants (heparin, LMWH and warfarin) and the most promising new anticoagulants (fondaparinux, idraparinux, rivaroxaban, apixaban, dabigatran and ximelagatran) by discussing their pharmacodynamics and pharmacokinetics. We also discuss recent patents in the field of anticoagulation, which aim to improve the safety and effectiveness of antithrombotic agents currently in use or offer alternative ways for anticoagulation.

Topics: Animals; Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; Dabigatran; Factor Xa; Factor Xa Inhibitors; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Morpholines; Oligosaccharides; Polysaccharides; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Thrombin; Warfarin

Venous thromboembolism is the most frequent preventable cause of death in hospitalized patients. Currently available anticoagulants have limitations that restrict their widespread use, particularly in long-term indications. Vitamin K antagonists require frequent monitoring and dose adjustment, and have a narrow therapeutic window with the risk of bleeding. The low-molecular-weight heparins have more predictable pharmacokinetics and pharmacodynamics, and coagulation monitoring is not required. However, their subcutaneous administration limits their suitability for long-term use. Consequently, many patients fail to receive effective preventive therapy. Rivaroxaban, apixaban, and dabigatran are new anticoagulants in late-stage clinical development that inhibit a single, specific coagulation factor, unlike the Vitamin K antagonists and low-molecular-weight heparins. Studies suggest that they provide effective, predictable anticoagulation with a low bleeding risk and will potentially offer an improved clinical profile and wider safety margin compared with currently available therapies.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; Blood Coagulation; Dabigatran; Drug Evaluation; Factor Xa; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Thrombin; Venous Thromboembolism

Acutely ill medical patients are at moderate to high risk of venous thromboembolism (VTE): approximately 10-30% of general medical patients may develop deep-vein thrombosis or pulmonary embolism, and the latter is a leading contributor to deaths in hospital. Medical conditions associated with a high risk of VTE include cardiac disease, cancer, respiratory disease, inflammatory bowel disease, rheumatological and infectious diseases. Pre-disposing risk factors in medical patients include a history of VTE, history of malignancy, complicating infections, increasing age, thrombophilia, prolonged immobility and obesity. Hence active cancer and a history of cancer are both strongly related to VTE in medical (non-surgical) patients. Heparins, both unfractionated (UFH) and low molecular weight (LMWH) and fondaparinux have been shown to be effective agents in prevention of VTE in this setting. However, it has not yet been possible to demonstrate a significant effect on mortality rates in this population. In medical patients, unfractionated heparin has a higher rate of bleeding complications than low molecular weight heparin. Thromboprophylaxis has been shown to be effective in medical patients with cancer and may have an effect on cancer outcomes. Thromboprophylaxis in patients receiving chemotherapy remains controversial and requires further investigation. There is no evidence for the use of aspirin, warfarin or mechanical methods. We recommend either low molecular weight heparin or fondaparinux as safe and effective agents in the thromboprophylaxis of medical patients.

Topics: Anticoagulants; Aspirin; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Morpholines; Neoplasms; Polysaccharides; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism; Warfarin

Cancer-associated thrombosis is a major cause of morbidity and mortality. Although anticoagulation remains the mainstay for prevention and treatment of thrombosis, current anticoagulants are problematic in cancer patients. Parenteral anticoagulants, such as heparin or low-molecular heparin, require daily subcutaneous injection, whereas warfarin requires coagulation monitoring and frequent dose adjustments. Idrabiotaparinux, a reversible long-acting pentasaccharide, and new oral anticoagulants, such as dabigatran etexilate, rivaroxaban and apixaban, have been designed to replace warfarin for extended prevention or treatment of VTE. Clinical trials with these agents have yielded promising results, and dabigatran etexilate and rivaroxaban are already licensed in many countries for thromboprophylaxis after elective hip or knee replacement surgery. In the coming years, these drugs are likely to replace warfarin for most indications. This paper addresses their potential role for prevention and treatment of cancer-related thrombosis.

Topics: Anticoagulants; Benzimidazoles; Biotin; Clinical Trials as Topic; Dabigatran; Humans; Morpholines; Neoplasms; Oligosaccharides; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Thrombosis

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

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

Oral warfarin is associated with extensive food and drug interactions, and there is a need to consider such interactions with the new oral anticoagulants (OACs) dabigatran etexilate, rivaroxaban and apixaban. A literature survey was conducted using PubMed, EMBASE and recent abstracts from thrombosis meetings to identify publications related to food, drug and dietary supplement interaction studies with dabigatran etexilate, rivaroxaban and apixaban. Clinical experience regarding food interactions is currently limited. Regarding drug-drug interactions, dabigatran requires caution when used in combination with strong inhibitors or inducers of P-glycoprotein, such as amiodarone or rifampicin. Rivaroxaban (and possibly apixaban) is contraindicated in combination with drugs that strongly inhibit both cytochrome P450 3A4 and P-glycoprotein, such as azole antimycotics, and caution is required when used in combination with strong inhibitors of only one of these pathways. Important drug interactions of the new OACs that can lead to adverse clinical reactions may also occur with non-steroidal anti-inflammatory drugs and antiplatelet drugs, such as aspirin and clopidogrel. Over-the-counter (OTC) medications and food supplements (e.g. St. John's Wort) may also interact with the new OACs. Given the common long-term use of drugs for some chronic disorders, the frequent use of OTC medications and the need for multiple treatments in special populations, such as the elderly people, it is essential that the issue of drug interactions is properly evaluated. New OACs offer significant potential advantages to the field of venous thromboprophylaxis, but we should not fail to appreciate their lack of extensive clinical experience.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Cytochrome P-450 Enzyme System; Dabigatran; Drug Interactions; Food-Drug Interactions; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes

Topics: Animals; Anticoagulants; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Factor Xa Inhibitors; Humans; Intracranial Thrombosis; Macaca fascicularis; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Venous Thrombosis

Many years of practical use and intensive scientific research have allowed vitamin K antagonists to become a cornerstone of treatment of internal diseases. Nevertheless, limitations in pharmacokinetics and -dynamics of vitamin K antagonists and the availability of new drugs in regard to a targeted anticoagulation therapy ask for a new review of the situation. Proof of effectiveness for the perioperative prophylaxis of venous thrombosis after hip and knee replacement has already been achieved for the direct thrombin inhibitor dabigatran etexilate as well as for the factor Xa inhibitors rivaroxaban und apixaban compared to low molecular weight heparins. These new drugs are now also investigated in patients with internal diseases. For the long-term application (6 or 12 months) concerning the treatment of venous thrombosis and/or stroke prophylaxis in patients with atrial fibrillation data is already available for the direct thrombin inhibitor dabigatran etexilate. Depending on its dosage its effectiveness in comparison with vitamin K antagonists is equal or even better without disadvantages in safety. However, vitamin K antagonists will remain the standard oral anticoagulation until open questions regarding e.g. insufficient therapy adherence (with termination rates up to 20%) or problems with drug interactions of the new competitive products have been completely answered.

Topics: Anticoagulants; Antithrombin Proteins; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Atrial Fibrillation; Benzimidazoles; Dabigatran; Humans; Morpholines; Postoperative Complications; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiophenes; Venous Thrombosis; Vitamin K

The traditional agents used for thromboprophylaxis are effective and safe but have limitations particularly related to ease of administration. Newer agents targeting single coagulation factors such as the direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban and apixaban have demonstrated efficacy and safety for thromboembolism prophylaxis in the orthopedic population and have the additional benefit of oral administration and predictable pharmacokinetics. Pharmacology of the new anticoagulants and published data on the use of these agents in total knee and hip replacement patients will be reviewed in this article.

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Benzimidazoles; Dabigatran; Humans; Morpholines; Postoperative Complications; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism

The past decade has witnessed an explosion in the clinical development of new orally-administered anticoagulant drugs aimed at complementing vitamin K antagonists and heparins for the prevention and treatment of venous thromboembolism, for the prevention of stroke in patients with chronic atrial fibrillation, and for treatment of acute coronary syndromes. This review will focus on those new oral anticoagulants that are most relevant to the practicing clinician. These drugs consist of dabigatran, a direct thrombin inhibitor and rivaroxaban, a factor Xa inhibitor, both of which have been recently approved for clinical use. In addition, apixaban will be reviewed, which is another factor Xa inhibitor that is in the final stages of clinical development. The objectives of this review are: 1) to provide a clinician-oriented overview of the key pharmacokinetic and pharmacodynamic properties of dabigatran, rivaroxaban and apixaban; 2) to consider the implications of these drugs' pharmacologic properties in the perioperative setting for patients who require elective or urgent surgery, focusing on pre- and post-operative dosing, laboratory monitoring and reversal of anticoagulant effect.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Drug Interactions; Drugs, Investigational; Humans; Morpholines; Perioperative Care; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes

Heparin and low molecular weight heparins have limitations in their efficacy and safety for the prevention and treatment of venous thromboembolism (VTE). New synthetic antithrombotic drugs, designed with the intention of improving the therapeutic window for prophylaxis and treatment, are in various stages of development. Synthetic pentasaccharides include fondaparinux and its long-acting analogue idraparinux. Dabigatran is a direct thrombin inhibitor that has undergone clinical trials for VTE prophylaxis and treatment. Direct factor Xa inhibitors include rivaroxiban, which has shown promising results for VTE prophylaxis and is being studied for VTE treatment, as well as apixaban and betrixaban, which are at earlier stages of clinical validation. These newer agents may represent viable options for prophylaxis and therapy as further clinical studies are performed.

Topics: Anticoagulants; Benzamides; Benzimidazoles; beta-Alanine; Dabigatran; Fondaparinux; Humans; Morpholines; Oligosaccharides; Polysaccharides; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiophenes; Venous Thromboembolism

The most frequent cardiac arrhythmia and main cause for cardio-embolic stroke is atrial fibrillation. Prophylaxis for thrombembolic events is performed regarding individual risk of patients with either ASS or vitamin-K-antagonists. Efficacy and safety of oral anticoagulation is limited by a narrow therapeutical range as well as by inter- and intraindividual variability of INR-values due to genetic disposition, differences in alimentation, dosage errors, rare control of INR-levels and drug-interactions. New oral anticoagulants with different mechanisms of action may be a promising therapeutic option in future. This review addresses the new anticoagulants Apixaban, Rivaroxban and Dabigatranetexilat with the design and as available the results of the corresponding phase-III-trials in atrial fibrillation (ARISTOTLE, ROCKET-AF, RE-LY).

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Azetidines; Benzimidazoles; Benzylamines; Clinical Trials, Phase III as Topic; Dabigatran; Factor Xa Inhibitors; Fibrinolytic Agents; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiophenes; Thromboembolism

For the past five decades, there has been little progress in the development of oral anticoagulants, with the choices being limited to the vitamin K antagonists (VKAs). The situation is changing with the development of orally active small molecules that directly target thrombin or activated factor X (FXa). The two agents in the most advanced stages of development are dabigatran etexilate and rivaroxaban, which inhibit thrombin and FXa, respectively. Both are approved in the EU and Canada for venous thromboprophylaxis in patients undergoing elective hip- or knee-replacement surgery. Other agents in the early stages of development include several FXa inhibitors (apixaban, DU 176b, LY 517717, YM 150, betrixaban, eribaxaban [PD 0348292] and TAK 442) and one thrombin inhibitor (AZD 0837). With a predictable anticoagulant response and low potential for drug-drug interactions, these new agents can be given in fixed doses without coagulation monitoring. This renders them more convenient than VKAs. While the anticoagulant effect of the new thrombin and FXa inhibitors is similar, differences in the pharmacokinetic and pharmacodynamic parameters may influence their use in clinical practice. Here, we compare the pharmacokinetic and pharmacodynamic features of these new oral agents.

Topics: Animals; Antithrombin III; Benzimidazoles; Dabigatran; Drug Discovery; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Thrombin

The treatment of choice for acute venous thromboembolism is anticoagulant therapy with fast-acting drugs (unfractionated or low-molecular-weight heparin or fondaparinux) aimed at preventing thrombus extension, followed by extended prophylaxis with vitamin K antagonists aimed at preventing recurrence. Experience accumulated over the years has demonstrated that strict laboratory monitoring is required for unfractionated heparin and vitamin K antagonists, making use of these drugs problematic for patients and physicians and prompting researchers to develop new anticoagulants equally effective but without the requirement for laboratory monitoring. The results of clinical trials to date, albeit limited, suggest that these new drugs will probably keep their promise. However, the definitive answer will come subsequent to these clinical trials, when clinicians will start to use these drugs to treat patients in the real world. It is likely that some sort of laboratory monitoring will be required at least for selected categories of patients. Accordingly, clinical laboratories should still be prepared to monitor patients, although the numbers may hopefully decrease sharply in the next decade or so.

Topics: Anticoagulants; Blood Coagulation; Clinical Trials as Topic; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Incidence; International Normalized Ratio; Monitoring, Physiologic; Morpholines; Polysaccharides; Prothrombin Time; Pulmonary Embolism; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism; Venous Thrombosis; Vitamin K

The use of pharmacological thromboprophylaxis in the perioperative period may conflict with regional anesthetic techniques in which maintaining hemostatic integrity is essential. Recently, new anticoagulants have been developed with more efficacy and a better safety profile. This article reviews the basis for the actual recommendations and the current status and management of these new drugs.. Recent studies have outlined that the risk of epidural hematoma after neuraxial anesthesia may be higher than estimated. Therefore, it is imperative to follow the published recommendations. The use of new anticoagulant drugs may take into account the pharmacological profile of each one to safely perform regional anesthesia, mainly the time to reach peak plasma level and half-life.. When new anticoagulant drugs are used for thromboprophylaxis in orthopedic surgery, the performance of neuraxial anesthetic techniques should be based on their pharmacology. If a peripheral blockade is chosen, these recommendations should be followed when a block is performed in a noncompressible area.

Topics: Anesthesia, Epidural; Anesthesia, Spinal; Anticoagulants; Benzimidazoles; Dabigatran; Hematoma, Epidural, Spinal; Humans; Morpholines; Nerve Block; Platelet Aggregation Inhibitors; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes

For more than 50 years, heparin and vitamin K antagonists (VKAs) have been the anticoagulant drugs used to prevent and treat thrombosis. Low molecular weight heparins (LMWHs) are more recent and have been available for approximately 20 years. Patients with cancer are members of a unique patient population because of their high risk for thrombosis and the risk of anticoagulant-related bleeding. With the currently available antithrombotic agents, patients with cancer still have unmet needs in terms of the prevention and treatment of thrombosis. Although long-term LMWH is the treatment of choice for patients with cancer who have acute, symptomatic venous thromboembolism (VTE), some patients still experience recurrent VTE. More effective antithrombotic agents are needed for such patients. Convenient (ie, oral and with no laboratory monitoring), effective, and safe agents are needed to prevent thrombosis in patients taking chemotherapy and antiangiogenic drugs and in patients with central vein catheters. There are a number of new antithrombotic agents that have been studied in recent years and will soon be available for certain diseases. They target either activated factor X (ie, factor Xa) or activated thrombin, and some of them have potential therapeutic value in patients with cancer. In this article, the clinical research model used for the development of a new antithrombotic agent is discussed along with the results of recent trials that evaluate these new agents in high-risk populations.

Topics: Administration, Oral; Anticoagulants; Dose-Response Relationship, Drug; Drug Administration Schedule; Factor Xa; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Humans; Injections, Subcutaneous; Male; Morpholines; Neoplasms; Prognosis; Pyrazoles; Pyridones; Rivaroxaban; Severity of Illness Index; Survival Analysis; Thiophenes; Treatment Outcome; Venous Thromboembolism

Atrial fibrillation is already the most common clinically significant cardiac arrhythmia and a common cause of stroke. Vitamin K antagonists are very effective for the prevention of cardioembolic stroke but have numerous limitations that limit their uptake in eligible patients with AF and reduce their effectiveness in treated patients. Multiple new anticoagulants are under development as potential replacements for vitamin K antagonists. Most are small synthetic molecules that target factor IIa (e.g., dabigatran etexilate, AZD-0837) or factor Xa (e.g., rivaroxaban, apixaban, betrixaban, DU176b, idrabiotaparinux). These drugs have predictable pharmacokinetics that allow fixed dosing without laboratory monitoring, and are being compared with vitamin K antagonists or aspirin in phase III clinical trials [corrected]. A new vitamin K antagonist (ATI-5923) with improved pharmacological properties compared with warfarin is also being evaluated in a phase III trial. None of the new agents have as yet been approved for clinical use.

Topics: Anticoagulants; Atrial Fibrillation; Benzamides; Benzimidazoles; Biotin; Clinical Trials, Phase III as Topic; Dabigatran; Factor Xa Inhibitors; Humans; Morpholines; Oligosaccharides; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Vitamin K

Important clinical data with a significant impact on the clinical management of venous thromboembolism (VTE) were presented at The International Society of Thrombosis and Haemostasis (ISTH) meeting, held in Geneva, Switzerland in July of 2007. In addition, 2 new guidelines for the management of patients with acute coronary syndromes (ACS) were published in 2007, and will have a significant impact on daily practice. Finally, the approval of new practice-changing, paradigm-shifting oral anticoagulants is on the horizon. This article will review the top 4 advances in antithrombotic care and discuss their impact on the clinical management of VTE.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Benzimidazoles; Clinical Trials as Topic; Dabigatran; Humans; Morpholines; Practice Guidelines as Topic; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism

Advances in antithrombotic therapy began when traditional anticoagulant agents such as heparin and the vitamin K antagonists like Coumadin became commercially available in the 1940s and 1950s. Inherent limitations of these compounds, including the need for monitoring and multiple food and drug interactions (with coumadin), spurred the development of newer parenteral compounds like low molecular weight heparin, the pentasaccharide fondaparinux, and direct thrombin inhibitors such as hirudin, argatroban and bivalirudin with advantages over traditional compounds. Despite the failure of the first oral anticoagulant in 50 years--the direct thrombin inhibitor ximelagatran--due to issues with liver toxicity, new oral agents such as the Factor Xa inhibitors rivaroxaban, apixaban, YM-150, and DU-176b and oral direct thrombin inhibitors such as dabigatran are in advanced stages of development, with dabigatran and rivaroxaban now approved for use outside of the United States for thromboprophylaxis in the setting of orthopedic surgery. These and other novel agents have the potential to greatly expand our armamentarium to treat thromboembolic disease, with more targeted approaches to specific procoagulant complexes, a predictable anticoagulant response that does not require monitoring, and use in both acute and long-term treatment settings.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; Dabigatran; Drug Discovery; Factor Xa Inhibitors; Humans; Morpholines; Oligosaccharides; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiophenes; Venous Thromboembolism

In Western countries, venous thromboembolism (VTE) is a widespread and serious disorder, with hospital admission rates that appear to be increasing. Current anticoagulant therapies available for the prevention and treatment of VTE have several drawbacks that make them either difficult to manage effectively, due to a need for careful monitoring to control coagulation, or, in the case of parenterally administered agents, inconvenient for long-term use. To address some of these issues, new anticoagulants are in clinical development that can be orally administered and directly target specific factors in the coagulation cascade. This article reviews the rationale behind development of these novel agents and provides a critical appraisal of their clinical potential. In addition, the impact that the introduction of such agents into clinical practice would have is discussed from the patient perspective.

Topics: Administration, Oral; Benzimidazoles; Blood Coagulation; Dabigatran; Fibrinolytic Agents; Hemorrhage; History, 20th Century; History, 21st Century; Humans; Medication Adherence; Morpholines; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Rivaroxaban; Thiophenes; Treatment Outcome; Venous Thromboembolism

Anticoagulant therapy is the cornerstone of treatment of venous thromboembolism (VTE). Such treatment is divided into 2 stages: Rapid initial anticoagulation is given to minimize the risk of thrombus extension and fatal pulmonary embolism, whereas extended anticoagulation is aimed at preventing recurrent VTE, thereby reducing the risk of postphlebitic syndrome. With currently available drugs, immediate anticoagulation can only be achieved with parenteral agents, such as heparin, low-molecular-weight heparin, or fondaparinux. Extended treatment usually involves the administration of vitamin K antagonists, such as warfarin. Emerging anticoagulants have the potential to streamline VTE treatment. These agents include idraparinux, a long-acting synthetic pentasaccharide that is given subcutaneously on a once-weekly basis, and new oral anticoagulants that target thrombin or factor Xa. This article (1) reviews the pharmacology of these agents, (2) outlines their potential strengths and weaknesses, (3) describes the results of clinical trials with these new drugs, and (4) identifies the evolving role of new anticoagulants in the management of VTE.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dabigatran; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Injections, Subcutaneous; Male; Maximum Tolerated Dose; Morpholines; Oligosaccharides; Postphlebitic Syndrome; Prognosis; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Survival Analysis; Thiophenes; Treatment Outcome; Venous Thromboembolism

Indirect systemic and direct oral factor Xa and direct oral factor IIa inhibitors with improved pharmacologic profiles compared with heparins and vitamin K antagonists are currently in clinical development. This overview focuses on the indirect antithrombin dependent pentasaccharide derivatives of idraparinux and on the most advanced oral direct inhibitors to factor Xa (rivaroxaban and apixaban) and IIa (dabigatran). Specifically, the results of dose-finding studies for the prevention of venous thromboembolism after elective orthopedic surgery, the results of dose-finding studies for treatment of acute venous thromboembolism including prolonged prophylaxis of recurrent events, and the designs of ongoing clinical trials are reviewed.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzimidazoles; Benzylamines; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Glycine; Humans; Infusions, Parenteral; Morpholines; Oligosaccharides; Piperazines; Prothrombin; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Thrombin; Thrombosis; Venous Thromboembolism

Topics: Angina, Unstable; Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; Brain Ischemia; Clinical Trials as Topic; Coumarins; Dabigatran; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Forecasting; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Morpholines; Myocardial Infarction; Peptide Fragments; Polysaccharides; Prothrombin; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiophenes; Thrombin; Thrombophilia; Thrombosis; Warfarin

Ciraparantag is a reversal agent for anticoagulants including direct oral anticoagulants. The aim was to evaluate the efficacy and safety of ciraparantag to reverse anticoagulation induced by apixaban or rivaroxaban in healthy elderly adults.. Two randomized, placebo-controlled, dose-ranging trials conducted in healthy subjects aged 50-75 years. Subjects received apixaban (Study 1) 10 mg orally twice daily for 3.5 days or rivaroxaban (Study 2) 20 mg orally once daily for 3 days. At steady-state anticoagulation subjects were randomized 3:1 to a single intravenous dose of ciraparantag (Study 1: 30, 60, or 120 mg; Study 2: 30, 60, 120, or 180 mg) or placebo. Efficacy was based on correction of the whole blood clotting time (WBCT) at multiple timepoints over 24 h. Subjects and technicians performing WBCT testing were blinded to treatment. Complete reversal of WBCT within 1 h post-dose and sustained through 5 h (apixaban) or 6 h (rivaroxaban) was dose related and observed with apixaban in 67%, 100%, 100%, and 17% of subjects receiving ciraparantag 30 mg, 60 mg, 120 mg, or placebo, respectively; and with rivaroxaban in 58%, 75%, 67%, 100%, and 13% of subjects receiving ciraparantag 30 mg, 60 mg, 120 mg, 180 mg, or placebo, respectively. Adverse events related to ciraparantag were mild, transient hot flashes or flushing.. Ciraparantag provides a dose-related reversal of anticoagulation induced by steady-state dosing of apixaban or rivaroxaban. Sustained reversal was achieved with 60 mg ciraparantag for apixaban and 180 mg ciraparantag for rivaroxaban. All doses of ciraparantag were well tolerated.

Topics: Administration, Oral; Adult; Aged; Anticoagulants; Arginine; Dabigatran; Healthy Volunteers; Humans; Middle Aged; Piperazines; Pyrazoles; Pyridones; Rivaroxaban

Although apixaban and rivaroxaban are commonly used in patients with atrial fibrillation (AF) and valvular heart disease (VHD), there is limited evidence comparing the 2 drugs in these patients.. To emulate a target trial of effectiveness and safety of apixaban and rivaroxaban in patients with AF and VHD.. New-user, active comparator, cohort study design.. Commercial health insurance database from 1 January 2013 to 31 December 2020.. New users of apixaban or rivaroxaban who had a diagnosis of AF and VHD before initiation of anticoagulant therapy.. The primary effectiveness outcome was a composite of ischemic stroke or systemic embolism. The primary safety outcome was a composite of gastrointestinal or intracranial bleeding. Cox proportional hazards regression with a robust variance estimator was used to estimate hazard ratios (HRs) and 95% CIs.. When compared with rivaroxaban in a propensity score-matched cohort of 19 894 patients (9947 receiving each drug), apixaban was associated with a lower rate of ischemic stroke or systemic embolism (HR, 0.57 [95% CI, 0.40 to 0.80]) and bleeding (HR, 0.51 [CI, 0.41 to 0.62]). The absolute reduction in the probability of stroke or systemic embolism with apixaban compared with rivaroxaban was 0.0026 within 6 months and 0.011 within 1 year of treatment initiation. The absolute reduction in the probability of bleeding events with apixaban compared with rivaroxaban was 0.012 within 6 months and 0.019 within 1 year of treatment initiation.. Short follow-up time and inability to ascertain some types of VHD.. In this study of patients with AF and VHD, patients receiving apixaban had a lower risk for ischemic stroke or systemic embolism and for bleeding when compared with those receiving rivaroxaban.. National Institutes of Health.

Topics: Anticoagulants; Atrial Fibrillation; Cohort Studies; Embolism; Heart Valve Diseases; Hemorrhage; Humans; Ischemic Stroke; Rivaroxaban; Stroke

Emergent cardiac surgery in patients under anticoagulant therapy is still a major point of concern. Recently approved reversal agents are often not available or not suitable in the cardiac surgery setting, and timely discontinuation of the drug is not always feasible. CytoSorb® haemoadsorption therapy has been approved in Europe for intraoperative ticagrelor and rivaroxaban removal during cardiopulmonary bypass (CPB), but thus far the efficacy of CytoSorb® haemoadsorber on other anticoagulants (apixaban, dabigatran, edoxaban) has only been tested in vitro, and some signals of clinical benefits have reported in a few case reports.. We describe a case of CPB implementation with CytoSorb® in a haemodynamic unstable patient with prosthetic aortic valve endocarditis on apixaban therapy.. CytoSorb® proved to be effective for removal of apixaban in emergency surgery setting by direct measurements of drug levels before and during CPB circulation.

Topics: Anticoagulants; Dabigatran; Humans; Pyridones; Rivaroxaban

Direct oral anticoagulants (DOACs) are frequently prescribed for the management of atrial fibrillation and venous thrombosis. There is a lack of published data on the utilization of DOACs in individuals who have undergone recent cardiac surgery. The purpose of this study was to evaluate the safety and efficacy of apixaban and rivaroxaban compared to warfarin in patients postcardiac surgery.. In this retrospective cohort study, patients were separated into a DOAC cohort or a warfarin cohort based on the agent they received after cardiac surgery. Patients could be included if they were ≥18 years of age and received or were discharged on either rivaroxaban, apixaban, or warfarin within 7 days after cardiac surgery. The primary outcome for the study was the rate of International Society on Thrombosis and Hemostasis (ISTH) major bleeding during hospitalization and for 30 days following discharge or until first follow-up appointment.. There were a total of 194 patients included in the analysis, 97 in the DOAC cohort and 97 in the warfarin cohort. Four patients (4.1%) in the DOAC group experienced ISTH major bleeding, while 2 patients (2.1%) in the warfarin cohort experienced ISTH major bleeding (p = 0.68). No patients in the DOAC cohort experienced a thrombotic event, whereas 2 patients (2.1%) in the warfarin cohort experienced a thrombotic complication (p = 0.5).. Apixaban and rivaroxaban demonstrated similar safety when compared to a matched cohort of warfarin patients. Larger prospective randomized studies are needed to confirm these findings.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Cardiac Surgical Procedures; Dabigatran; Hemorrhage; Humans; Prospective Studies; Retrospective Studies; Rivaroxaban; Stroke; Warfarin

ST Genesia is a new automated system enabling quantitative standardized evaluation of thrombin generation (TG), for example, in patients receiving anti-Xa direct inhibitors (xabans). Data on its analytical performances are scarce.. Over an 18-month period, repeatability, reproducibility, and accuracy were assessed using STG-ThromboScreen (without or with thrombomodulin) or STG-DrugScreen reagents (corresponding to intermediate/high tissue-factor concentration, respectively), and controls. Furthermore, reproducibility was assessed using commercialized lyophilized and frozen normal pooled plasmas. Rivaroxaban and apixaban impacts on TG parameters were assessed using spiking experiments. Finally, a comparison with the Calibrated Automated Thrombogram method (CAT) (PPP reagent) was performed using plasma from healthy volunteers enrolled in the DRIVING-studyNCT01627665) before and after rivaroxaban intake.. For all dedicated quality control (QC) levels, inter-series coefficients of variations (CV) were <7% for temporal TG parameters, peak height (PH), and endogenous thrombin potential (ETP), whether results were normalized with a dedicated reference plasma STG-RefPlasma or not. Noteworthy, STG-RefPlasma used for normalization displayed substantially high PH and ETP. Mean biases between the observed and manufacturer's assigned QC values were mostly <7%. Both rivaroxaban/apixaban plasma concentrations were significantly associated with TG parameters. Finally, Bland-Altman plots showed a good agreement between ST Genesia-STG-ThromboScreen and CAT method within the explored range of values, although biases could be observed (PH: 16.4 ± 13.2%, ETP: 17.8 ± 11.9%).. ST Genesia

Topics: Blood Coagulation; Blood Coagulation Tests; Factor Xa Inhibitors; Humans; Pyrazoles; Pyridones; Reproducibility of Results; Rivaroxaban; Thrombin

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Chromatography, High Pressure Liquid; Cross-Sectional Studies; Cyclophosphamide; Drug Monitoring; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Pilot Projects; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Tandem Mass Spectrometry

Andexanet alfa is a recombinant modified human FXa (factor Xa) developed to reverse FXa inhibition from anticoagulants. Hemostatic efficacy and reversal of anti-FXa activity with andexanet were assessed in patients from the ANNEXA-4 study (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXa Inhibitors) with intracranial hemorrhage (ICrH).. ANNEXA-4 was a single-arm study evaluating andexanet in patients presenting with major bleeding ≤18 hours after taking an FXa inhibitor. Patients received a bolus plus 2-hour infusion of andexanet. Brain imaging in patients with ICrH was performed at baseline and at 1 and 12 hours postandexanet infusion. Coprimary efficacy outcomes were change in anti-FXa activity and hemostatic efficacy at 12 hours (excellent/good efficacy defined as ≤35% increase in hemorrhage volume/thickness). Safety outcomes included occurrence of thrombotic events and death at 30 days.. A total of 227 patients with ICrH were included in the safety population (51.5% male; mean age 79.3 years) and 171 in the efficacy population (99 spontaneous and 72 traumatic bleeds). In efficacy evaluable patients, excellent/good hemostasis 12 hours postandexanet occurred in 77 out of 98 (78.6%) and in 58 out of 70 (82.9%) patients with spontaneous and traumatic bleeding, respectively. In the subanalysis by FXa inhibitor treatment group in the efficacy population, median of percent change in anti-FXa from baseline to nadir showed a decrease of 93.8% for apixaban-treated patients (n=99) and by 92.6% for rivaroxaban-treated patients (n=59). Within 30 days, death occurred in 34 out of 227 (15.0%) patients and thrombotic events occurred in 21 out of 227 (9.3%) patients (safety population).. Andexanet reduced anti-FXa activity in FXa inhibitor-treated patients with ICrH, with a high rate of hemostatic efficacy. Andexanet may substantially benefit patients with ICrH, the most serious complication of anticoagulation.. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02329327.

Topics: Aged; Aged, 80 and over; Blood Coagulation Factor Inhibitors; Factor Xa; Female; Hemostasis; Humans; Intracranial Hemorrhages; Male; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban

Mechanical thrombectomy (MT) is one of the main treatments for acute ischemic stroke (AIS) in patients on effective anticoagulation. The use of direct oral anticoagulants (DOA) has increased, given their efficacy and safety profile compared to vitamin K antagonists (VKA). We compared procedural and clinical outcomes of MT in patients on DOA and VKA treatment before stroke onset. We analyzed 2 groups from the Endovascular Treatment in Ischemic Stroke prospective registry: patients on DOA and patients on VKA treated by MT without thrombolysis. Generalized linear mixed models including center as random effect were used to compare angiographic (rates of reperfusion at end of procedure, number of passes >2, procedural complications) and clinical (favorable and excellent outcome, 90-day all-cause mortality, and hemorrhagic complications) outcomes according to anticoagulation subgroups. Comparisons were adjusted for prespecified confounders (age, admission NIH Stroke Scale score) as well as for meaningful baseline between-group differences. Among 221 patients included, more DOA-treated patients (n = 115, 52%) achieved successful (modified Thrombolysis in Cerebral Infarction score [mTICI] 2b/3) or near complete (mTICI 2c/3) reperfusion at the procedure end than did VKA-treated patients, with an adjusted odds ratio (OR) for DOA vs VKA of 3.27 (95% confidence interval [CI], 1.40-7.65) and 2.00 (95% CI, 1.08-3.73), respectively. DOA-treated patients had a lower 90-day mortality risk with an adjusted OR of 0.47 (95% CI, 0.24-0.89) and a better excellent outcome OR of 2.40 (1.10-5.27). There was no significant between-group difference in hemorrhagic or procedural complications. The study highlights the benefits of DOA compared to VKA. Regarding mortality, excellent outcomes, and recanalization rate, DOA appears to provide a favorable setting for MT treatment in AIS.

Topics: Aged; Anticoagulants; Dabigatran; Female; Hemorrhage; Humans; Male; Pyrazoles; Pyridones; Registries; Reperfusion; Rivaroxaban; Stroke; Thrombectomy; Treatment Outcome; Vitamin K

To measure direct factor Xa inhibitor (apixaban, edoxaban, rivaroxaban) concentrations, dedicated chromogenic anti-Xa assays are recommended as suitable methods to provide rapid drug quantification. Moreover, the high-performance liquid chromatography with ultraviolet detection (HPLC-UV) is reported as a reliable quantitative technique. We investigated seven anti-Xa assays and an HPLC-UV method for measurement of apixaban and rivaroxaban levels in patients enrolled in the START-Register.. A total of 127 apixaban and 124 rivaroxaban samples were tested by HPLC-UV and the following anti-Xa assays: Biophen DiXaI and Heparin LRT (Hyphen BioMed), Berichrom and Innovance Heparin (Siemens), STA-Liquid Anti-Xa (Stago Diagnostics), Technochrom anti-Xa (Technoclone), and HemosIL Liquid Anti-Xa (Werfen). Each method was performed in one of the participating laboratories: Bologna, Cremona, Florence, and Padua.. Our data confirmed the overestimation of apixaban and rivaroxaban levels by the antithrombin-supplemented anti-Xa method (Berichrom). Performances and reproducibility of the six anti-Xa assays not supplemented with antithrombin and the HPLC-UV method were good, with limits of quantification from 8-39 ng/mL (apixaban) and 15-33 ng/mL (rivaroxaban). The six chromogenic methods showed good concordances with the quantitative HPLC-UV [bias: -26.9-22.3 ng/mL (apixaban), -11.3-18.7 ng/mL (rivaroxaban)]. Higher bias and wider range between limits of agreement were observed at higher concentrations [<100 ng/mL: bias -21.3-4.1 ng/mL (apixaban) and -6.2-3.8 ng/mL (rivaroxaban); >200 ng/mL: bias -42.2-36.8 ng/mL (apixaban) and -20.1-68.9 ng/mL (rivaroxaban)].. Overall, the anti-Xa assays not supplemented with antithrombin and the HPLC-UV method proved to be suitable for apixaban and rivaroxaban quantification.

Topics: Chromatography, High Pressure Liquid; Drug Monitoring; Factor Xa Inhibitors; Female; Humans; Male; Pyrazoles; Pyridones; Registries; Rivaroxaban

Although randomized trials provide a high level of evidence regarding the efficacy of non-vitamin K oral anticoagulants (NOACs), the results of such trials may differ from those observed in day-to-day clinical practice.. To compare the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) between NOAC and warfarin in clinical practice.. Patients with non-valvular atrial fibrillation (NVAF) who started warfarin/NOACs between January 2015 and November 2016 were retrospectively identified from Korea's nationwide health insurance claims database. Using inpatient diagnosis and imaging records, the Cox models with inverse probability of treatment weighting using propensity scores were used to estimate hazard ratios (HRs) for NOACs relative to warfarin.. Of the 48,389 patients, 10,548, 11,414, 17,779 and 8,648 were administered apixaban, dabigatran, rivaroxaban and warfarin, respectively. Many patients had suffered prior strokes (36.7%, 37.7%, 31.4%, and 32.2% in apixaban, dabigatran, rivaroxaban, and warfarin group, respectively), exhibited high CHA2DS2-VASc (4.8, 4.6, 4.6, and 4.1 in apixaban, dabigatran, rivaroxaban, and warfarin group, respectively) and HAS-BLED (3.7, 3.6, 3.6, and 3.3 in apixaban, dabigatran, rivaroxaban, and warfarin group, respectively) scores, had received antiplatelet therapy (75.4%, 75.7%, 76.8%, and 70.1% in apixaban, dabigatran, rivaroxaban, and warfarin group, respectively), or were administered reduced doses of NOACs (49.8%, 52.9%, and 42.8% in apixaban, dabigatran, and rivaroxaban group, respectively). Apixaban, dabigatran and rivaroxaban showed a significantly lower S/SE risk [HR, 95% confidence intervals (CI): 0.62, 0.54-0.71; 0.60, 0.53-0.69; and 0.71, 0.56-0.88, respectively] than warfarin. Apixaban and dabigatran (HR, 95% CI: 0.58, 0.51-0.66 and 0.75, 0.60-0.95, respectively), but not rivaroxaban (HR, 95% CI: 0.84, 0.69-1.04), showed a significantly lower MB risk than warfarin.. Among Asian patients who were associated with higher bleeding risk, low adherence, and receiving reduced NOAC dose than that provided in randomised controlled trials, all NOACs were associated with a significantly lower S/SE risk and apixaban and dabigatran with a significantly lower MB risk than warfarin.

Topics: Administration, Oral; Adult; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Embolism; Female; Hemorrhage; Humans; Male; Middle Aged; Proportional Hazards Models; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Vitamin K; Warfarin

Activated clotting time (ACT)-guided heparinization is used during atrial fibrillation (AF) ablation. Differences in sensitivity to ACT assays have been identified among different direct oral anticoagulants (DOACs).. We aimed to examine ACT just before ablation (pre-ACT) for different ablation start times (9:00, 11:00, 13:00, or 15:00) and ablation safety outcomes in minimally interrupted (min-Int) and uninterrupted (Unint) DOAC regimens and examine differences in pre-ACT values among four DOACs.. Consecutive patients were randomized into the min-Int (n = 307) or Unint (n = 277) groups. DOACs examined were apixaban, dabigatran, edoxaban, and rivaroxaban.. No sequential changes in pre-ACT values were observed for each DOAC used and for all four DOACs combined in the min-Int and Unint groups. There was no meaningful difference in pre-ACT at each ablation start time between the groups. Clinically significant differences in overall pre-ACT were not obtained between the groups (138 ± 24 vs 142 ± 23 seconds). The pre-ACT (baseline) value for dabigatran was on average 29 seconds higher than that for the other three DOACs. The min-Int and Unint groups showed similar thromboembolic (0% vs 0%) and bleeding event rates (major, 1% vs 0%; all, 3.5% vs 2.5%).. The pre-ACT did not show a sequential change in the min-Int and Unint groups. No notable differences in the time-dependent change in pre-ACT between the groups were observed. Variations in baseline ACT suggest the need for moderate adjustment of ACT for adequate modification of heparin dose for the other three DOACs. Both regimens provided similar acceptable AF ablation safety outcomes.

Topics: Action Potentials; Aged; Antithrombins; Atrial Fibrillation; Blood Coagulation; Catheter Ablation; Dabigatran; Drug Administration Schedule; Drug Monitoring; Factor Xa Inhibitors; Female; Heart Rate; Humans; Japan; Male; Middle Aged; Predictive Value of Tests; Pyrazoles; Pyridines; Pyridones; Risk Factors; Rivaroxaban; Thiazoles; Time Factors; Treatment Outcome; Whole Blood Coagulation Time

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

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

Direct oral anticoagulants (DOACs) are frequently used for the treatment of pulmonary embolism (PE), but both clinical and laboratory data comparing their efficacy and safety are conflicting. This study investigated and compared the impact of three DOACs (apixaban, rivaroxaban and dabigatran) on coagulation cascade in acute PE patients.. After the initial treatment, acute PE patients were randomly allocated to one of three groups, and treatment continued using one of the three DOACs. Following 1 month of treatment, the activity of factors II, VII and VIII, as well as protein C, antithrombin, D-dimer and fibrinogen, were measured, and the values were compared between the groups.. One hundred consecutive PE patients were included. The mean values for the activity of factors II and VII and protein C were higher in patients on apixaban than in patients on rivaroxaban (1.45 ± 1.12 (IU/mL) vs 1.13 ± 0.92 (IU/mL), P < 0.001; 1.24 ± 1.10 (IU/mL) vs 1.05 ± 0.98 (IU/mL), P = 0.024 and 1.15 ± 0.62 vs 1.02 ± 0.68 (IU/mL), P = 0.019, respectively). The mean of factor II activity and the median of factor VIII activity were also significantly higher in patients on apixaban than in patients on dabigatran (1.45 ± 1.12 vs 1.20 ± 0.96 (IU/mL), P = 0.003 and 2.9 (2.0-4.0) vs 2.1 (1.5-2.7) (IU/mL), P = 0.001, respectively). No difference was noticed in D-dimer concentrations, or in the activity of the other factors measured. Additionally, no difference was noticed between the rivaroxaban and dabigatran groups.. Apixaban had a significantly higher thrombin activity, above the laboratory determined normal range, compared to patients on rivaroxaban and dabigatran. This higher thrombin activity in patients on apixaban may contribute to a better haemostatic response during the therapy or increased prothrombotic state after therapy interruption.

Topics: Acute Disease; Administration, Oral; Adult; Aged; Anticoagulants; Blood Coagulation Factors; Dabigatran; Female; Humans; Male; Middle Aged; Pulmonary Embolism; Pyrazoles; Pyridones; Rivaroxaban; Thrombin; Treatment Outcome

Although a recent expert consensus statement has recommended periprocedural uninterrupted (UI) non-vitamin K antagonist oral anticoagulants (NOACs) during catheter ablation of atrial fibrillation (AF) as a Class I indication, there have been no clear randomized trials. We investigated the safety and efficacy of UI, procedure day single-dose skipped (SDS), and 24-hour skipped (24S) NOACs in patients undergoing AF ablation.. In this prospective, open-label, randomized multicentre trial, 326 patients (75% male, 58 ± 11 years old) scheduled for AF catheter ablation were randomly assigned in a 1:1:1 ratio to UI, SDS, and 24S at three tertiary hospitals. Bridging with low molecular weight heparin was carried out in the patients with persistent AF who were assigned to the 24S group. Dabigatran, rivaroxaban, and apixaban were assigned in order after randomization. The primary endpoint was the incidence of bleeding events within 1 month after ablation. The secondary endpoints included thrombo-embolic and other procedure-related complications. The intra-procedural heparin requirement was higher in the 24S group than others (P < 0.001), and the mean activated clotting time was comparable among the groups (P = 0.139). The incidence of major bleeding up to 1 month after ablation and a post-procedural reduction in the haemoglobin levels did not significantly differ among the treatment groups and different NOACs (P > 0.05). There were no fatal events or thrombo-embolic complications in all the three groups.. In patients undergoing AF ablation, UI NOACs and SDS or double dose skipped NOACs had a comparable efficacy and safety, regardless of the type of NOAC.

Topics: Aged; Anticoagulants; Antithrombins; Atrial Fibrillation; Catheter Ablation; Dabigatran; Drug Administration Schedule; Embolism; Factor Xa Inhibitors; Female; Hemorrhage; Heparin; Humans; Incidence; Intraoperative Care; Male; Middle Aged; Preoperative Care; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Whole Blood Coagulation Time

The aim of this study was to prove the suitability of simultaneously administered microdoses of the factor Xa inhibitors (FXaIs) rivaroxaban, apixaban and edoxaban (100 µg in total). To evaluate drug-drug interactions, the impact of ketoconazole, a known strong inhibitor of cytochrome P450 3A4 and P-glycoprotein, was studied.. In a crossover clinical trial, 18 healthy volunteers were randomized to the two treatments using microdoses of rivaroxaban, apixaban and edoxaban alone and when coadministered with ketoconazole. Plasma and urine concentrations of microdosed apixaban, edoxaban and rivaroxaban were quantified using a validated ultra-performance liquid chromatography-tandem mass spectrometry assay with a lower limit of quantification of 2.5 pg/ml.. The microdosed FXaI cocktail showed similar pharmacokinetic parameters compared with published data, using normal therapeutic doses of each FXaI. Ketoconazole significantly increased exposure, with geometric mean AUC ratios of 1.90 (apixaban), 2.35 (edoxaban) and 2.27 (rivaroxaban).. The microdosed FXaI cocktail approach was able to precisely predict the drug interaction with ketoconazole. This is the first study that has been conducted to evaluate drug-drug interactions with a drug class, and the low administered doses also allow evaluation in vulnerable target populations.. EudraCT 2016-003024-23.

Topics: Administration, Oral; Adolescent; Adult; Atrial Fibrillation; Case-Control Studies; Chromatography, Liquid; Cross-Over Studies; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Factor Xa Inhibitors; Female; Humans; Ketoconazole; Male; Middle Aged; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Tandem Mass Spectrometry; Thiazoles; Young Adult

Practice-based investigations on direct oral anticoagulant (DOAC) treatment for non-valvular atrial fibrillation (NVAF) have shown that off-label under-dosing is increasingly becoming an issue. Here, we investigate the significance of drug monitoring to prevent undesirable under-dosing with DOAC. Methods and Results: In 255 outpatients with NVAF undergoing treatment with rivaroxaban or apixaban we estimated the cut-offs for bleeding events using drug plasma concentration (PC) data 3 h after drug treatment, that is, at the peak level. Furthermore, we evaluated the appropriateness of labeled and off-label dosing implemented for 348 patients using the obtainable PC threshold. A total of 73 off-label under-dose users of rivaroxaban (37% of all users and 63% of lower dose users) had acceptable peak PC (155-400 ng/mL). Additionally, 46 off-label under-dose users of apixaban (31% of all users and 55% of lower dose users) received appropriate doses according to peak PC threshold (90-386.4 ng/mL). These off-label under-dose users reported no bleeding or thromboembolic events during follow-up.. Anticoagulation monitoring enables personalized and appropriate off-label under-dosing in NVAF patients on rivaroxaban or apixaban through the measurement of peak PC during DOAC use.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Drug Monitoring; Female; Humans; Male; Middle Aged; Off-Label Use; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban

To provide direct comparison between apixaban and rivaroxaban in patients with acute cancer-associated venous thromboembolism (Ca-VTE), consecutive patients treated with apixaban, rivaroxaban, or enoxaparin at Mayo Thrombophilia Clinic (March 1, 2013 to January 31, 2018)) were followed prospectively. The primary effectiveness outcome was venous thromboembolism (VTE) recurrence, and the secondary was mortality. The primary safety outcome was major bleeding, the secondary clinically relevant safety outcome was non-major bleeding (CRNMB), and the third a composite of major and CRNMB. There were 750 patients treated for acute Ca-VTE with apixaban (n = 224), rivaroxaban (n = 163), and enoxaparin (n = 363) within 14 days of diagnosis and for at least 3 months, or until study event. Recurrent VTE was diagnosed in 11 receiving apixaban, 7 receiving rivaroxaban (apixaban vs rivaroxaban hazard ratio (HR) 1.31, 95% confidence interval (95% CI) 0.51-3.36) and 17 in the enoxaparin receiving group (apixaban vs enoxaparin HR 1.14, 95% CI: 0.54, 2.42 and rivaroxaban vs enoxaparin HR 0.85, 95% Cl: 0.36, 2.06). There were 82 deaths in apixaban, 74 rivaroxaban (apixaban vs rivaroxaban HR 1.67, 95% Cl: 1.20, 2.33) and 171 in enoxaparin group (rivaroxaban vs enoxaparin HR 0.73, 95% Cl: 0.56, 0.96). Major bleeding occurred in 11 apixaban, 12 rivaroxaban (apixaban vs rivaroxaban HR 0.73, 95% Cl: 0.32, 1.66) and 21 enoxaparin group (apixaban vs enoxaparin HR 0.89, 95% Cl: 0.43, 1.84 and rivaroxaban vs enoxaparin HR 1.23, 95% Cl: 0.61, 2.50). The CRNMB rate was higher in rivaroxaban compared to apixaban (P = .03) and LMWH (P = .01) groups. Recurrence of VTE and major bleeding were similar in apixaban, rivaroxaban, and enoxaparin groups. Rivaroxaban was associated with higher CRNMB but lower mortality compared to apixaban and enoxaparin.

Topics: Aged; Anticoagulants; Enoxaparin; Factor Xa Inhibitors; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Neoplasms; Propensity Score; Prospective Studies; Pulmonary Embolism; Pyrazoles; Pyridones; Recurrence; Rivaroxaban; Survival Analysis; Treatment Outcome; Venous Thromboembolism

There is no established method for monitoring the anticoagulant effects of apixaban and rivaroxaban. Linear correlation between serum levels and anti-Xa activity has been shown, with r. To evaluate the anti-Xa activity and serum levels at those doses and compare the trough anti-Xa activity.. This was a single-center prospective study,approved by the institutional review board. Patients on an inappropriate dose or receiving an interacting drug were excluded. Blood samples were drawn 0.5 to 3 hours before a dose for both agents, 2 to 3 hours after an apixaban dose, and 12 to 16 hours after a rivaroxaban dose. Anti-Xa activity and serum levels were determined, and correlation was done via regression analysis. Trough anti-Xa activity was compared using a t-test.. Good correlation was shown between anti-Xa activity and serum levels. The clinical utility of monitoring anti-Xa activity and the significance of the difference in trough anti-Xa activity for these agents remains to be established.

Topics: Aged; Factor Xa; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban

The availability of direct oral anticoagulants has caused a paradigm shift in the management of thrombosis. Rivaroxaban and apixaban are 2 direct oral anticoagulants whose target specificity is activated factor X (FXa). However, it is still not fully understood if and how xabans impact platelet function. This observational study aimed to assess the in vitro platelet function in patients with atrial fibrillation receiving xabans. This was a single-center study quantifying platelet aggregation in 41 patients treated with apixaban or rivaroxaban by light transmission aggregometry. The thrombin receptor activating peptide (TRAP)-induced platelet aggregation was significantly lower 2 hours after taking rivaroxaban or apixaban compared to baseline value (56.15% [8.53%] vs 29.51% [12.9%]; P = .000). Moreover, concomitant use of angiotensin-converting enzyme blockers, proton pump inhibitors, and statins reduces the efficiency of xabans. The TRAP-induced platelet aggregation was reduced in patients with cardiovascular disease 2 hours after receiving xabans.

Topics: Aged; Aged, 80 and over; Atrial Fibrillation; Female; Humans; Male; Middle Aged; Peptide Fragments; Platelet Aggregation; Platelet Function Tests; Pyrazoles; Pyridones; Rivaroxaban; Time Factors

To evaluate the effect of telemonitoring on adherence to non-vitamin K antagonist oral anticoagulants (NOACs) in atrial fibrillation (AF) patients.. A randomized, single-blind, crossover, controlled trial in 48 AF patients on once or twice daily (OD or BID) NOAC. The Medication Event Monitoring System tracked NOAC intake during three phases of 3 months each: daily telemonitoring, telemonitoring with immediate telephone feedback in case of intake errors, and an observation phase without daily transmissions. Unprotected days were defined as ≥ 3 or ≥ 1 consecutively missed doses for a BID or OD NOAC, respectively, or excess dose intake. Cost-effectiveness was calculated based on anticipated stroke reduction derived from patients' risk profile and measured intake. Persistence over the entire study was 98%. Telemonitoring-only already led to very high taking and regimen adherence (97.4% respectively 93.8%). Nevertheless, direct feedback further improved both to 99.0% and 96.8%, respectively (P < 0.001 respectively P = 0.002). Observation without daily monitoring resulted in a significant waning of taking adherence (94.3%; P = 0.049). Taking adherence was significantly higher for OD compared to BID NOAC, although unprotected days were similar. Feedback intervention had an incremental cost of €344 289 to prevent one stroke, but this could be as low as €15 488 in high-risk patients with low adherence and optimized technology.. Telemonitoring resulted in high NOAC adherence due to the notion of being watched, as evidenced by the rapid decline during the observation period. Feedback further optimized adherence. Telemonitoring with or without feedback may be a cost-effective approach in high-risk patients deemed poorly adherent.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Cost-Benefit Analysis; Cross-Over Studies; Feedback; Female; Humans; Male; Medication Adherence; Monitoring, Ambulatory; Pyrazoles; Pyridones; Rivaroxaban; Single-Blind Method; Stroke

Little data exist on the use of direct oral anticoagulant (DOAC) factor Xa inhibitors for submassive pulmonary embolism (PE) after catheter-directed thrombolysis (CDT). The objective of this evaluation was to determine whether the transition from parenteral anticoagulation to DOACs for submassive PE after CDT would decrease hospital length of stay (LOS) compared to warfarin.. A retrospective review of patients diagnosed with submassive PE who underwent CDT was conducted from January 1, 2012, to February 28, 2017. Hospital LOS and major and minor bleeding events were recorded during hospitalization and at 90 days.. Sixty-two patients met the inclusion criteria, 36 in warfarin group and 26 in the DOAC group. Overall, patients receiving rivaroxaban or apixaban had a shorter median hospital LOS compared to warfarin (4.0 vs 6.1 days, P = .002). In the multivariate regression analysis, administration of DOAC was an independent predictor of decreased hospital LOS, β: -2.1, 95% confidence interval (-3.5 to -0.7).. Among patients with submassive PE, initiation of a DOAC shortly after CDT may result in a decreased hospital LOS compared to parenterally bridged warfarin.

Topics: Aged; Female; Humans; Length of Stay; Male; Middle Aged; Pulmonary Embolism; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Thrombolytic Therapy; Warfarin

Direct acting non-Vitamin K antagonist oral anticoagulants (NOAC) are characterized by a fixed dosing regimen. Despite the potential for relative underdosing due to large distribution volumes, dose adjustments for patients with high body mass index (BMI) are not recommended. Since efficacy and safety data in obese patients are scarce, we evaluated the impact of BMI on clinical outcomes in daily care patients treated with NOAC for stroke prevention in atrial fibrillation or venous thromboembolism. Using prospectively collected data from a non-interventional registry, cardiovascular (CV), major bleeding events (MB) and all-cause mortality were evaluated according to BMI classes. All outcome events were centrally adjudicated using standard scientific definitions. Between November 1st 2011 and December 31st 2016, 3432 patients were enrolled into the registry (61.3% rivaroxaban; 20% apixaban; 10.1% dabigatran, 8.6% edoxaban; mean follow-up 998.1 ± 542.9 days; median 1004 days). With increasing BMI (range 13.7-57.2 kg/m

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Body Mass Index; Dabigatran; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Male; Obesity; Prospective Studies; Pyrazoles; Pyridines; Pyridones; Registries; Rivaroxaban; Thiazoles; Thromboembolism; Treatment Outcome; Vitamin K

Nonvitamin K oral anticoagulants (NOACs) sometimes cause hemorrhage, and the gastrointestinal tract is a common site of involvement. However, clinical characteristics of gastrointestinal bleeding (GIB) during NOAC therapy have not been fully elucidated. We studied 658 patients who were prescribed dabigatran, rivaroxaban, or apixaban between April 2011 and November 2015. Medical charts were reviewed to examine whether clinically relevant bleeding (Bleeding Academic Research Consortium criteria type 2 or greater) developed. The incidence of GIB was 2.0%/year, and one-third was from the upper GI. Among all hemorrhagic events, GIB was the most common cause. The extent of bleeding from the GI tract, particularly the upper GI tract, was more serious than bleeding from the other site. Multiple regression analysis showed that both past digestive ulcer and absence of concomitant proton pump inhibitors were significantly associated with the incidence of upper GIB, while concomitant nonsteroidal anti-inflammatory drugs, dual antiplatelets, and past GIB were significant factors regarding lower GIB. GIB was common and serious in patients taking NOACs. Upper GIB tended to become more serious than lower GIB. Proton pump inhibitors seem to be key drugs for preventing upper GIB during NOAC therapy.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Dabigatran; Female; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Proton Pump Inhibitors; Pyrazoles; Pyridones; Rivaroxaban

Many patients requiring cardiac implantable electronic device (CIED) implantation are on long-term oral anticoagulant therapy. While continuation of warfarin has been shown to be safe and reduce bleeding complications compared to interruption of warfarin therapy and heparin bridging, it is not known which novel oral anticoagulants (NOAC) regimen (interrupted vs uninterrupted) is better in this setting.. One-hundred and one patients were randomized to receive CIED implantation with either interrupted or uninterrupted/continuous NOAC therapy before surgery. No heparin was used in either treatment arm. The primary end-point was the presence of a clinically significant pocket hematoma after CIED implantation. The secondary end-point was a composite of other major bleeding events, device-related infection, thrombotic events, and device-related admission length postdevice implantation.. Both treatment groups were equally balanced for baseline variables and concomitant medications. One clinically significant pocket hematoma occurred in the uninterrupted NOAC group and none in the interrupted group (P  =  0.320). There was no difference in other bleeding complications. No thrombotic events were observed in either of the two groups.. Despite the paucity of bleeding events, data from this pilot study suggest that uninterrupted NOAC therapy for CIED implantation appears to be as safe as NOAC interruption and does not increase bleeding complications.

Topics: Administration, Oral; Aged; Anticoagulants; Antithrombins; Dabigatran; Factor Xa Inhibitors; Female; Humans; Male; Pacemaker, Artificial; Pilot Projects; Prospective Studies; Prosthesis Implantation; Pyrazoles; Pyridones; Rivaroxaban; Single-Blind Method; Warfarin

Our aim is to determine the most appropriate laboratory tests, besides anti-factor Xa (anti-FXa) chromogenic assays, to estimate the degree of anticoagulation with apixaban and compare it with that of rivaroxaban in real-world patients. Twenty patients with nonvalvular atrial fibrillation treated with apixaban 5 mg twice daily and 20 patients on rivaroxaban 20 mg once daily were studied. Conventional coagulation tests, thrombin generation assay (TGA), and thromboelastometry (nonactivated TEM [NATEM] assay) were performed in the 40 patients and 20 controls. The anti-FXa chromogenic assays were used to measure apixaban and rivaroxaban plasma levels. The NATEM measurements showed no significant difference between the 2 groups of patients. Concerning TGA, endogenous thrombin potential (ETP) was significantly decreased in patients on rivaroxaban as compared to those treated with apixaban (

Topics: Aged; Anticoagulants; Atrial Fibrillation; Female; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban; Thrombelastography; Thrombin

Guidelines recommend warfarin continuation rather than heparin bridging for pacemaker and defibrillator surgery, after the BRUISE CONTROL trial demonstrated an 80% reduction in device pocket haematoma with this approach. However, direct oral anticoagulants (DOACs) are now used to treat the majority of patients with atrial fibrillation. We sought to understand the best strategy to manage the DOACs at the time of device surgery and specifically hypothesized that performing device surgery without DOAC interruption would result in a reduced haematoma rate.. We randomly assigned patients with atrial fibrillation and CHA2DS2-VASc score ≥2, to continued vs. interrupted DOAC (dabigatran, rivaroxaban, or apixaban). The primary outcome was blindly evaluated, clinically significant device pocket haematoma: resulting in re-operation, interruption of anticoagulation, or prolonging hospital stay. In the continued arm, the median time between pre- and post-operative DOAC doses was 12 h; in the interrupted arm the median time was 72 h. Clinically significant haematoma occurred in of 7 of 328 (2.1%; 95% CI 0.9-4.3) patients in the continued DOAC arm and 7 of 334 (2.1%; 95% CI 0.9-4.3) patients in the interrupted DOAC arm (P = 0.97). Complications were uncommon, and included one stroke and one symptomatic pericardial effusion in each arm.. These results suggest that, dependent on the clinical scenario, either management strategy (continued DOAC or interrupted DOAC) might be reasonable, at least for patients similar to those enrolled in our trial.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Cardiac Pacing, Artificial; Dabigatran; Defibrillators, Implantable; Drug Administration Schedule; Female; Hematoma; Humans; Length of Stay; Male; Middle Aged; Postoperative Complications; Pyrazoles; Pyridones; Reoperation; Rivaroxaban; Thromboembolism

Several non-vitamin K antagonist oral anticoagulant (NOAC) alternatives to warfarin are available for stroke prevention in atrial fibrillation (AF). We aimed to describe the factors associated with selection of NOACs versus warfarin in patients with new onset AF.. The ORBIT-AF II study is a national, US, prospective, observational, cohort study of anticoagulation treatment in patients with AF receiving NOACs or warfarin in the United States from 2013 to 2016. We measured factors associated with oral anticoagulant selection in 4,670 patients recently diagnosed with AF.. At baseline, 1,169 (25%) patients were started on warfarin and 3,501 (75%) on NOACs: of these latter, 259 (6%) were started on dabigatran, 1858 (40%) on rivaroxaban, and 1384 (30%) on apixaban. Those receiving NOACs were slightly younger patients (median age 71 vs 72, P<.0001); were less likely to have prior stroke (5.3% vs 8.6%; P<.0001) or prior bleeding (2.7% vs 4.4%; P=.005); had better kidney function (mean estimated glomerular filtration rate 91 mL/min vs 80 mL/min, P<.0001); and had fewer patients at high stroke risk (CHA. In contemporary clinical practice, up to three-fourths of patients with new-onset AF are now initially treated with a NOAC for stroke prevention. Those selected for NOAC treatment had lower stroke and bleeding risk profiles, were more likely treated by cardiologists, and had higher socioeconomic status.. clinicaltrials.gov Identifier: NCT01701817.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Factor Xa Inhibitors; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prospective Studies; Pyrazoles; Pyridones; Registries; Risk Factors; Rivaroxaban; Stroke; Treatment Outcome; Vitamin K; Warfarin

Essentials In this crossover study the anticoagulant effects of rivaroxaban and apixaban were compared. Healthy volunteers received rivaroxaban 20 mg once daily or apixaban 5 mg twice daily. Rivaroxaban was associated with more prolonged inhibition of thrombin generation than apixaban. Rivaroxaban induced a clear prolongation of prothrombin time and activated partial thromboplastin time.. Background The anticoagulant actions of the oral direct activated factor Xa inhibitors, rivaroxaban and apixaban, have not previously been directly compared. Objectives To compare directly the steady-state pharmacokinetics and anticoagulant effects of rivaroxaban and apixaban at doses approved for stroke prevention in patients with non-valvular atrial fibrillation. Methods Twenty-four healthy Caucasian male volunteers were included in this open-label, two-period crossover, phase 1 study (EudraCT number: 2015-002612-32). Volunteers were randomized to receive rivaroxaban 20 mg once daily or apixaban 5 mg twice daily for 7 days, followed by a washout period of at least 7 days before they received the other treatment. Plasma concentrations and anticoagulant effects were measured at steady state and after drug discontinuation. Results Overall exposure was similar for both drugs: the geometric mean area under the plasma concentration-time curve for the 0-24-h interval was 1830 μg h L

Topics: Adult; Blood Coagulation; Cross-Over Studies; Drug Administration Schedule; Factor Xa Inhibitors; Germany; Healthy Volunteers; Humans; Male; Middle Aged; Partial Thromboplastin Time; Predictive Value of Tests; Prothrombin Time; Pyrazoles; Pyridones; Reproducibility of Results; Rivaroxaban; Thrombin; Young Adult

Background The perioperative management of patients who take a direct oral anticoagulant (DOAC) for atrial fibrillation and require treatment interruption for an elective surgery/procedure is a common clinical scenario for which best practices are uncertain. The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) study is designed to address this unmet clinical need. We discuss the rationale for the PAUSE design and analysis plan as well as the rationale supporting the perioperative DOAC protocol.\ \ Methods PAUSE is a prospective study with three parallel cohorts, one for each DOAC, to assess a standardized but patient-specific perioperative management protocol for DOAC-treated patients with atrial fibrillation. The perioperative protocol accounts for DOAC type, patient's renal function and surgery/procedure-related bleeding risk. The primary study aim is to demonstrate the safety of the PAUSE protocol for the perioperative management of each DOAC. The secondary aim is to determine the effect of the pre-procedure interruption on residual anticoagulation when measured by the dilute thrombin time for dabigatran and anti-factor Xa levels for rivaroxaban and apixaban. The study hypothesis is that the perioperative management protocol for each DOAC is safe for patient care, defined by expected risks for major bleeding of 1% (80% power to exclude 2%), and for arterial thromboembolism of 0.5% (80% power to exclude 1.5%) in each DOAC group.\ \ Conclusion The PAUSE study has the potential to establish a standard-of-care approach for the perioperative management of DOAC-treated patients. The PAUSE management protocol is designed to be easily applied in clinical practice, as it is standardized and also patient specific.

Topics: Administration, Oral; Adult; Anticoagulants; Atrial Fibrillation; Canada; Cardiac Surgical Procedures; Cohort Studies; Dabigatran; Female; Hemorrhage; Humans; Male; Perioperative Period; Postoperative Complications; Precision Medicine; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban

We previously reported that dabigatran increased the risk of microthromboembolism and hemopericardium compared with warfarin. The safety of non-vitamin-K-antagonist oral anticoagulants (NOACs) in the periprocedural use of atrial fibrillation (AF) ablation is controversial. This study aimed to compare the incidence of asymptomatic cerebral microthromboembolism and hemopericardium in AF ablation among periprocedural use of rivaroxaban, apixaban, and warfarin.. This study was a prospective, randomized registry. Patients taking NOACs upon visiting our hospital were randomly assigned into 2 groups; rivaroxaban and apixaban. Warfarin was continued in patients taking warfarin. Asymptomatic cerebral microthromboembolism was evaluated by magnetic resonance imaging on the day after the ablation procedure. In 176 consecutive patients (101 paroxysmal, and 75 persistent AF), rivaroxaban was used in 55, apixaban in 51, and warfarin in 70. There were no symptomatic cerebral infarctions in this study. Asymptomatic cerebral microthromboembolism was detected in 32 (18.4%) patients; nine (16.4%) with rivaroxaban, 10 (20%, p=0.80; vs. rivaroxaban) with apixaban, and 13 (18.8%, p=0.81; vs. rivaroxaban) with warfarin. Hemopericardium occurred in 5 (2.8%) patients; 2 with rivaroxaban, 1 with apixaban (p=1.0; vs. rivaroxaban), and 2 with warfarin (p=1.0; vs. rivaroxaban). In multivariate analysis, concomitant coronary angiography (p<0.05, odds ratio 5.73) was a predictor of cerebral thromboembolism.. The incidence of asymptomatic cerebral microthromboembolism and hemopericardium in AF ablation is similar among the periprocedural use of rivaroxaban, apixaban, and warfarin.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Catheter Ablation; Combined Modality Therapy; Coronary Angiography; Factor Xa Inhibitors; Female; Humans; Incidence; Intracranial Thrombosis; Magnetic Resonance Angiography; Male; Middle Aged; Pericardial Effusion; Prospective Studies; Pyrazoles; Pyridones; Registries; Rivaroxaban; Warfarin

The results of the EINSTEIN-DVT/PE and AMPLIFY trials, which compared rivaroxaban and apixaban with conventional anticoagulation therapy for acute venous thromboembolism (VTE), respectively, are often compared. However, the trials differed in duration of therapy (3-12 and 6months, respectively) and in patient selection (few exclusion criteria and more stringent exclusion criteria, respectively).. To determine the effect of these methodological differences on outcomes, the patients enrolled in EINSTEIN-DVT/PE were divided into 2 cohorts; the 5253 patients that matched the exclusion criteria for AMPLIFY and were treated for at least 6months (cohort 1) and the 2368 patients who would have been ineligible for AMPLIFY (cohort 2).. Compared with patients in cohort 2, those in cohort 1 were older and more often male and there were more with unprovoked VTE, prior VTE, cancer and known thrombophilia. In cohort 1, rivaroxaban would have significantly reduced recurrent VTE (relative risk [RR], 0.64; 95% confidence interval [CI], 0.43-0.95) and major bleeding (RR, 0.50; 95% CI, 0.30-0.82) compared with conventional therapy, whereas the two treatments would have had similar effects on recurrent VTE (RR, 1.08; 95% CI, 0.65-1.79) and major bleeding (RR, 1.03; 95% CI, 0.48-2.18) in cohort 2.. This analysis illustrates the influence of patient selection and treatments duration on outcome results and highlights the limitations of cross-trial comparisons.

Topics: Adult; Aged; Cohort Studies; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Patient Selection; Pyrazoles; Pyridones; Rivaroxaban; Treatment Outcome; Venous Thromboembolism

Point-of-care testing (POCT) of coagulation has been proven to be of great value in accelerating emergency treatment. Specific POCT for direct oral anticoagulants (DOAC) is not available, but the effects of DOAC on established POCT have been described. We aimed to determine the diagnostic accuracy of Hemochron® Signature coagulation POCT to qualitatively rule out relevant concentrations of apixaban, rivaroxaban, and dabigatran in real-life patients.. We enrolled 68 patients receiving apixaban, rivaroxaban, or dabigatran and obtained blood samples at six pre-specified time points. Coagulation testing was performed using prothrombin time/international normalized ratio (PT/INR), activated partial thromboplastin time (aPTT), and activated clotting time (ACT+ and ACT-low range) POCT cards. For comparison, laboratory-based assays of diluted thrombin time (Hemoclot) and anti-Xa activity were conducted. DOAC concentrations were determined by liquid chromatography-tandem mass spectrometry.. Four hundred and three samples were collected. POCT results of PT/INR and ACT+ correlated with both rivaroxaban and dabigatran concentrations. Insufficient correlation was found for apixaban. Rivaroxaban concentrations at <30 and <100 ng/mL were detected with >95% specificity at PT/INR POCT ≤1.0 and ≤1.1 and ACT+ POCT ≤120 and ≤130 s. Dabigatran concentrations at <30 and <50 ng/mL were detected with >95% specificity at PT/INR POCT ≤1.1 and ≤1.2 and ACT+ POCT ≤100 s.. Hemochron® Signature POCT can be a fast and reliable alternative for guiding emergency treatment during rivaroxaban and dabigatran therapy. It allows the rapid identification of a relevant fraction of patients that can be treated immediately without the need to await the results of much slower laboratory-based coagulation tests.. Unique identifier, NCT02371070 . Retrospectively registered on 18 February 2015.

Topics: Anticoagulants; Blood Coagulation Tests; Dabigatran; Factor Xa Inhibitors; Humans; Partial Thromboplastin Time; Point-of-Care Systems; Prospective Studies; Prothrombin Time; Pyrazoles; Pyridones; Rivaroxaban; Thrombin Time

Limited data are available regarding safety of catheter ablation of atrial fibrillation (AF) in patients using novel oral anticoagulants (NOAC) before and after pulmonary vein isolation. We aimed to assess the safety of a simple anticoagulation protocol in consecutive patients presenting for catheter ablation of AF.. From November 2011 to December 2014, we prospectively included 234 patients referred for catheter ablation of AF who had already received NOAC treatment. NOAC was continued for a minimum of three months after ablation. We assessed procedure-related bleeding or thromboembolic complications, bleeding or thromboembolic complications during a three-month follow-up period and patient-reported adherence to NOAC therapy. The study has not received financial support from external resources. The study was registered with ClinTrials.gov as NCT02569255.. A total of 171 patients were treated with dabigatran (94% 150 mg twice daily), 38 with rivaroxaban (100% 20 mg daily) and 25 with apixaban (100% 5 mg twice daily). NOACs were interrupted for 24 hours before and re-administered two hours after the ablation procedure, without bridging with low molecular weight heparin (LMWH). No periprocedural thromboembolic complications and no bleeding complications were registered except for one pericardial effusion which was percutaneously drained without further complications. No thromboembolic or bleeding complications during follow-up were registered. All patients continued the same NOAC during follow-up as before ablation.. Anticoagulation with NOAC with a short period of periprocedural interruption without bridging with LMWH seems safe and well-tolerated.. none.. The trial is registered as ClinTrials.gov no. NCT01569255.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Catheter Ablation; Dabigatran; Female; Humans; Male; Middle Aged; Postoperative Hemorrhage; Prospective Studies; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Thromboembolism

Patients who require perioperative anticoagulation during cardiac implantable electronic device surgery are at increased risk for bleeding complications. The BRUISE CONTROL trial demonstrated that continuing warfarin was safer than heparin bridging, reducing the incidence of clinically significant pocket hematoma. Novel oral anticoagulants are being increasingly prescribed in place of warfarin. The best perioperative management of these new anticoagulants is unknown.. A randomized controlled trial to investigate whether a strategy of continued vs interrupted novel oral anticoagulant (dabigatran, rivaroxaban, or apixaban) at the time of device surgery, in patients with moderate to high risk of arterial thromboembolic events, reduces the incidence of clinically significant hematoma (defined as a hematoma requiring reoperation and/or resulting in prolongation of hospitalization, and/or requiring interruption of anticoagulation). The secondary outcomes include components of the primary outcome, composite of all other major perioperative bleeding events, thromboembolic events, all-cause mortality, cost-effectiveness, patient quality of life, perioperative pain, and satisfaction. Planned analyses include descriptive statistics of all baseline variables. For the primary outcome, interrupted vs continued novel oral anticoagulant arms will be compared using the χ(2) test. If any clinically significant differences are identified, a logistic regression analysis will be conducted. Quality of life will be assessed using EuroQol-5D, and perioperative pain using a visual analog scale.. BRUISE CONTROL-2 is a randomized trial evaluating the best strategy to manage novel oral anticoagulants at the time of device surgery. We hypothesize that device surgery can be performed safely without interruption of these medications.

Topics: Administration, Oral; Anticoagulants; Arrhythmias, Cardiac; Canada; Cause of Death; Dabigatran; Defibrillators, Implantable; Dose-Response Relationship, Drug; Hemorrhage; Humans; Incidence; Pacemaker, Artificial; Practice Guidelines as Topic; Preoperative Care; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban; Survival Rate; Thromboembolism; Warfarin

During atrial fibrillation ablation, heparin is required and is guided by the activated clotting time (ACT). Differences in the ACT before ablation and adequate initial heparin dosing in patients receiving non-vitamin K antagonist oral anticoagulants (NOACs) were examined.. Patients who received warfarin (control, N = 90), dabigatran etexilate (N = 90), rivaroxaban (N = 90) and apixaban (N = 90) were studied. A 100 U/kg dose of heparin was administered as a reliable control dose for warfarin, and the remaining patients were randomly administered 110, 120 or 130 U/kg of heparin in each NOAC group, followed by a continuous heparin infusion.. Periprocedural thromboembolic and major bleeding were not observed. Minor bleeding occurred rarely without significant differences among the groups examined. Baseline ACTs were longer in the warfarin (152 ± 16 s) and dabigatran (153 ± 13 s) groups than in the rivaroxaban (134 ± 13 s) and apixaban (133 ± 20 s) groups. The initial bolus heparin dosages required to produce an ACT 15 min after the initial bolus that was identical to the control (333 ± 32 s) were 120 U/kg (318 ± 29 s) and 130 U/kg (339 ± 43 s) for dabigatran, 130 U/kg (314 ± 31 s) for rivaroxaban and 130 U/kg (317 ± 39 s) for apixaban. The NOAC groups required significantly larger doses of total heparin than the warfarin group.. The baseline ACTs differed among the three NOAC groups. The results of the comparison with warfarin (the control) indicated that dosages of 120 or 130 U/kg for dabigatran, and 130 U/kg for rivaroxaban and apixaban, were adequate initial heparin dosages.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Catheter Ablation; Dabigatran; Female; Hemorrhage; Heparin; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban; Warfarin

Andexanet alfa (andexanet) is a recombinant modified human factor Xa decoy protein that has been shown to reverse the inhibition of factor Xa in healthy volunteers.. In this multicenter, prospective, open-label, single-group study, we evaluated 67 patients who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor. The patients all received a bolus of andexanet followed by a 2-hour infusion of the drug. Patients were evaluated for changes in measures of anti-factor Xa activity and were assessed for clinical hemostatic efficacy during a 12-hour period. All the patients were subsequently followed for 30 days. The efficacy population of 47 patients had a baseline value for anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.5 IU per milliliter for those receiving enoxaparin) and had confirmed bleeding severity at adjudication.. The mean age of the patients was 77 years; most of the patients had substantial cardiovascular disease. Bleeding was predominantly gastrointestinal or intracranial. The mean (±SD) time from emergency department presentation to the administration of the andexanet bolus was 4.8±1.8 hours. After the bolus administration, the median anti-factor Xa activity decreased by 89% (95% confidence interval [CI], 58 to 94) from baseline among patients receiving rivaroxaban and by 93% (95% CI, 87 to 94) among patients receiving apixaban. These levels remained similar during the 2-hour infusion. Four hours after the end of the infusion, there was a relative decrease from baseline of 39% in the measure of anti-factor Xa activity among patients receiving rivaroxaban and of 30% among those receiving apixaban. Twelve hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis (79%; 95% CI, 64 to 89). Thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up.. On the basis of a descriptive preliminary analysis, an initial bolus and subsequent 2-hour infusion of andexanet substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, with effective hemostasis occurring in 79%. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327 .).

Topics: Acute Disease; Aged; Aged, 80 and over; Cardiovascular Diseases; Enoxaparin; Factor Xa; Factor Xa Inhibitors; Female; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Infusions, Intravenous; Intracranial Hemorrhages; Male; Prospective Studies; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban; Thrombosis

Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors.. Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percent change in anti-factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant.. Among the apixaban-treated participants, anti-factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), as compared with 21% among those who received placebo (9 participants) (P<0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P<0.001) within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti-factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), as compared with 18% among those who received placebo (14 participants) (P<0.001), and unbound rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng per milliliter (P<0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P<0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic events were reported.. Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. (Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R ClinicalTrials.gov numbers, NCT02207725 and NCT02220725.).

Topics: Administration, Oral; Aged; Antidotes; Blood Coagulation; Double-Blind Method; Factor Xa; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Peptide Fragments; Protein Precursors; Prothrombin; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban

This study was designed to compare effectiveness and safety of warfarin, direct thrombin inhibitor dabigatran, Xa factor inhibitors rivaroxaban and apixaban used to prevent stroke in 280 elderly patients in patients with age-specific non-valvular atrial fibrillation. The treatment of patients aged 65-74 and 75-80 yearsfor 2 years with dab itragan (110 mg b.i.d), apixaban (5 mg b. i. d), and rivaroxaban (20 mg once daily) prevented stroke as effectively as warfarin therapy but less frequently caused severe intracranial hemorrhage. It is concluded that these new anticoagulants can be used as alternative medication for antithrombotic therapy of elderly patients with age-specific non-valvular atrialfibrillation.

Topics: Age Factors; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Drug Monitoring; Female; Humans; International Normalized Ratio; Intracranial Hemorrhages; Male; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Treatment Outcome; Warfarin

Dabigatran, rivaroxaban, and apixaban are direct oral anticoagulants (DOAC) inhibiting thrombin or factor Xa and effectively preventing thromboembolic complications using fixed doses without need for laboratory-guided dose adjustment. Plasma samples are needed to determine the actual concentration or activity of DOACs, which may be required for special patient populations such as those with acute deterioration of renal function due to any disease, before surgical interventions, during bleeding or thrombotic episodes while on therapy with DOACs, the elderly and youngest populations, unexpected pregnancy, suspicion of overdose and toxication, and to control adherence to therapy. Serum samples have several advantages over plasma samples such as no need of sampling with a specific coagulation tube, reduced pre-analytical errors, and longer storage stability. Determination of rivaroxaban and apixaban from serum samples of patients on treatment performed well and better than samples of patients treated with dabigatran compared with plasma samples. Specific adaption to automated coagulation platforms may improve the performance of the assays from serum samples.

Topics: Administration, Oral; Adult; Aged; Anticoagulants; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Morpholines; Pregnancy; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thrombin

Warfarin and aspirin are used to prevent stroke in patients with atrial fibrillation (AF). There are inherent challenges with both treatments, including variable and inconsistent benefit and increased bleeding risks. The availability of new anticoagulants offers some alternatives.. A mixed treatment comparison meta-analysis to evaluate direct and indirect treatment data including aspirin, warfarin apixaban, dabigatran, edoxaban, and rivaroxaban for the prevention of primary or secondary stroke in patients with AF.. A comprehensive, systematic literature search was conducted to identify randomized trials comparing aspirin, warfarin, apixaban, dabigatran, edoxaban, and rivaroxaban in patients with AF requiring treatment for stroke prevention. Open-label and blinded designs were included if they evaluated any stroke or any bleeding event. Data on stroke and bleeding events were abstracted, verified, evaluated, scored, and entered into Aggregate Data Drug Information System version 1.16 to generate a mixed treatment comparison meta-analysis. Direct and indirect comparisons were evaluated, and we looked for inconsistency in closed loop structures. Data are reported as rate ratios with 95% credible intervals. In addition, we reviewed variance statistics and explored variance with node-splitting models.. Our literature search yielded 30 articles, 21 of which were included. All treatments except aspirin reduced the risk of any stroke compared with placebo. Warfarin (0.43 [0.33-0.57]), apixaban (0.37 [0.27-0.54]), dabigatran (0.34 [0.21-0.57]), rivaroxaban (0.36 [0.22-0.60]), and aspirin with clopidogrel (0.73 [0.53-0.99]) were more protective than aspirin alone. Warfarin and the new anticoagulants were similar in the reduction of stroke, vascular death, and mortality. There was no difference in major bleeding between any treatment group. There were more nonmajor bleeding events when comparing warfarin and apixaban (1.83 [1.05-4.03]); no other differences between warfarin and the other new anticoagulants were found.. This mixed treatment comparison meta-analysis found similarity between warfarin and the new anticoagulants with the exception of one comparison, in which warfarin was associated with more non-major bleeding than apixaban. Thus, the new anticoagulants are therapeutically comparable when warfarin is inappropriate.

Topics: Anticoagulants; Aspirin; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Data Interpretation, Statistical; Databases, Bibliographic; Double-Blind Method; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Warfarin

To compare the main efficacy and safety endpoints of the pivotal randomised clinical trials (RCTs) on venous thromboembolism (VTE) prevention after total hip (THR) or knee (TKR) replacement with the new oral anticoagulants (NAs) versus enoxaparin.. A pool-analysis of 10 RCTs that included 32.144 randomised patients was performed. Efficacy outcomes were total VTE and all-cause mortality, major VTE, and proximal DVT. Safety outcomes were major bleeding, and clinically relevant (major or non-major) bleeding.. Overall, a significant effect favouring NAs was found for the primary efficacy outcome (RR 0.71; 95%CI 0.56-0.90), major VTE (RR 0.59; 95%CI 0.41-0.84), and proximal DVT (RR 0.51; 95%CI 0.35-0.76). Compared to enoxaparin 40 mg QD, rivaroxaban showed superiority (RR 0.50; 95%CI 0.34-0.73), followed by apixaban (RR 0.63; 95%CI 0.36-1.01) and dabigatran (RR 1.02; 95%CI 0.86-1.20). There was significant heterogeneity among trials and subgroups analysed for these efficacy outcomes. Major bleeding (RR 1.04; 95% CI 0.74-1.46) and clinically relevant bleeding (RR 1.03; 95%CI 0.88-1.21) was similar with NAs or enoxaparin. Rivaroxaban showed a trend toward more major bleeding episodes than enoxaparin (RR 1.88; 95%CI 0.92-3.82) and apixaban showed the lowest clinically relevant bleeding risk (RR 0.81; 95%CI 0.64-1.01).. Overall, NAs showed more efficacy and same safety when compared to the recommended dose of enoxaparin after THR and TKR. There are little differences in efficacy and bleeding risk among NAs and the type of prophylaxis that should be analysed further.

Topics: Adult; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Benzimidazoles; beta-Alanine; Dabigatran; Enoxaparin; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Treatment Outcome; Venous Thromboembolism

The purpose of this study is to determine the percentage of patients in the Johns Hopkins Anticoagulation Clinics that are potential candidates for the new oral anticoagulants, dabigatran, rivaroxaban, and apixaban. A retrospective chart review was conducted of patients managed in the Johns Hopkins Cardiology and Hematology Anticoagulation Clinics between November 1, 2009 and October 31, 2010. Data elements collected include demographics, primary indication for anticoagulation, renal function, hepatic function, and concomitant medications. These factors were considered against product labeling guidelines and inclusion/exclusion criteria from clinical studies to derive candidacy status for each oral anticoagulant for each patient. Patients who met at least one caution or contraindication criteria were deemed "non-candidates"; potential dosage reductions of the new oral anticoagulants were not considered. Four hundred ninety-one patients participated in the study. Among participants, 63% would be dabigatran candidates, 62% rivaroxaban candidates, and 70% would be candidates for apixaban. Dabigatran use would be cautioned against in 34%, rivaroxaban in 18 %, and apixaban in 30%. Four percent had contraindications to dabigatran, whereas 21% had contraindications to rivaroxaban. More than 60% of patients in the Johns Hopkins Anticoagulation Clinics appear to be potential candidates for each of the new oral anticoagulants, assuming they are eventually approved for the same indications as warfarin. Many patients fell into the "cautioned" category, which demonstrates the complexity associated with selecting candidates for these new agents.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Antithrombins; Benzimidazoles; beta-Alanine; Dabigatran; Female; Hospitals, University; Humans; Kidney Function Tests; Liver Function Tests; Male; Middle Aged; Morpholines; Practice Guidelines as Topic; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Thiophenes

Direct acting oral anticoagulants (DOAC) are now commonly prescribed medications. Urgent reversal of their anticoagulant effect is sometimes required in emergency situations. In Australia, a specific reversal agent for factor Xa (FXa)-inhibitor DOAC is not available. Instead, two non-specific haemostatic agents, activated prothrombin complex concentrate (aPCC) and 3 factor-prothrombin complex concentrate (3F-PCC), are used off-label despite a paucity of evidence for their effectiveness or safety.. To provide further insight into the efficacy and safety of 3F-PCC and aPCC for the reversal of the anticoagulant effect of FXa inhibitor DOACs.. We conducted a single-centre retrospective cohort study to investigate the use of aPCC and 3F-PCC for patients on FXa-inhibitor DOAC who present with a significant bleeding event or who require urgent surgery. The primary outcome was haemostatic efficacy according to prespecified criteria. Safety outcomes included the thromboembolic event rate and all-cause mortality during the hospital admission.. A total of 51 patients was included in the study (36 patients who had a spontaneous bleeding event and 15 non-bleeding patients who required urgent perioperative management). Thirty-one patients received aPCC and 20 patients received 3F-PCC. Haemostasis was adjudicated as effective in all assessable patients (n = 50; 100%). Thromboembolic events occurred in three patients who received aPCC and one patient who received 3F-PCC. All-cause mortality was 7.8% (four patients).. Both aPCC and 3F-PCC are useful adjuncts for the management of patients who require urgent reversal of the anticoagulant effect of FXa-inhibitor DOAC. However, the risk of thromboembolism in this patient group requires careful consideration. Prospective, comparator studies are needed along with the development of guidelines that reflect the availability of haemostatic agents in Australia.

Topics: Anticoagulants; Australia; Hemorrhage; Hemostatics; Humans; Prospective Studies; Retrospective Studies; Rivaroxaban; Thromboembolism

Topics: Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Hemorrhage; HIV Infections; Humans; Male; Pyridones; Ritonavir; Rivaroxaban; Stroke; Warfarin

This study attempts to identify predictors associated with bleeding and stroke and systemic embolism (SSE) in Singaporean Asians taking rivaroxaban and apixaban.. A total of 134 Singaporean patients on either rivaroxaban or apixaban for non-valvular atrial fibrillation were included for this study. Baseline characteristics were recorded at recruitment while bleeding and SSE events were recorded during a 1-year follow-up. Peak and trough drug plasma concentrations were collected based on the dosing interval and pharmacokinetics of the drugs and quantified using high performance liquid chromatography. Characteristics of patients with or without bleeds were compared using relevant statistical tests. Multivariable regression that included covariates with p < 0.1 from an initial univariable regression was performed to analyse predictors that resulted in higher risk of bleeding in patients.. Median creatinine clearance (CrCl) was significantly lower in patients on rivaroxaban who experienced bleeds as compared to patients who did not experience bleeds (61.5 vs 70.8 mL/min, p = 0.047), while concomitant simvastatin use was found to be independently associated with a sixfold increased risk of bleeding (adjusted OR = 6.14 (95% CI: 1.18-31.97), p = 0.031) for rivaroxaban after controlling for body mass index, CrCl and having experienced a previous SSE.. Our findings suggest that concomitant use of simvastatin with rivaroxaban may be associated with bleeding events in an Asian cohort. Further studies using physiologically based pharmacokinetic modelling are required to investigate the drug-drug interactions between these drugs.

Topics: Anticoagulants; Asian People; Atorvastatin; Atrial Fibrillation; Cohort Studies; Dabigatran; Drug Therapy, Combination; Hemorrhage; Humans; Rivaroxaban; Simvastatin; Singapore; Stroke

Compare costs associated with all-cause healthcare resource use (HCRU), stroke/systemic thromboembolism (STE) and major bleedings (MB) between patients with non-valvular atrial fibrillation (NVAF) initiating apixaban or other oral anticoagulants (OACs).. We performed a retrospective cohort study using the French healthcare claims database, including NVAF patients between 2014/01/01 and 2016/12/31, followed until 2016/12/31. We used 4 sub-cohorts of OAC-naive patients, respectively initiating apixaban, dabigatran, rivaroxaban or VKAs. We matched patients initiating apixaban with patients initiating each other OACs using 1:n propensity score matching. All-cause HCRU and event-related costs by OAC treatment were estimated and compared between matched patients using generalised-linear models with gamma-distribution and two-part models.. There were 175,766 patients in the apixaban-VKA, 181,809 in the apixaban-rivaroxaban, and 42,490 in the apixaban-dabigatran matched cohorts. Patients initiating apixaban had significantly lower HCRU costs than patients initiating VKA (€1,105 vs. €1,578, p < 0.0001), dabigatran (€993 vs. €1,140, p < 0.0001) and rivaroxaban (€1,013 vs. €1,088 p < 0.0001). They have had significantly lower costs related to stroke/STE and MB than patients initiating VKA (respectively, €183 vs. €449 and €147 vs. €413; p < 0.0001), rivaroxaban (respectively, €145 vs. €197 and €129 vs. €193; p < 0.0001), and lower costs related to stroke/STE than patients initiating dabigatran (€135 vs. €192, p < 0.02). Costs related to MB were not significantly different in patients initiating apixaban and those initiating dabigatran (€119 vs. €149, p = 0.07).. HCRU and most event-related costs were lower in patients initiating apixaban compared to other OACs. Apixaban may be cost-saving compared to VKAs, and significantly cheaper than other DOACs, although cost differences are limited.

Topics: Anticoagulants; Atrial Fibrillation; Dabigatran; France; Hemorrhage; Humans; Retrospective Studies; Rivaroxaban; Stroke

 Although a growing number of very elderly patients with atrial fibrillation (AF), multiple conditions, and polypharmacy receive direct oral anticoagulants (DOACs), few studies specifically investigated both apixaban/rivaroxaban pharmacokinetics and pharmacodynamics in such patients..  To investigate: (1) DOAC concentration-time profiles; (2) thrombin generation (TG); and (3) clinical outcomes 6 months after inclusion in very elderly AF in-patients receiving rivaroxaban or apixaban..  Adage-NCT02464488 was an academic prospective exploratory multicenter study, enrolling AF in-patients aged ≥80 years, receiving DOAC for at least 4 days. Each patient had one to five blood samples at different time points over 20 days. DOAC concentrations were determined using chromogenic assays. TG was investigated using ST-Genesia (STG-ThromboScreen, STG-DrugScreen)..  Our study provides original data in very elderly patients receiving DOAC in a real-life setting, showing great inter-individual variability in plasma concentrations and TG parameters. Further research is needed to understand the potential clinical impact of these findings.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Humans; Prospective Studies; Pyridones; Rivaroxaban; Stroke; Thrombin

The purpose of this study was to evaluate and compare clinical outcomes in patients who experienced intracranial hemorrhage (ICH) while taking apixaban or rivaroxaban and were reversed with four-factor prothrombin complex concentrates (4F-PCC) or andexanet alfa (AA). This retrospective cohort included adult patients that received 4F-PCC or AA for the initial management of an apixaban- or rivaroxaban-associated ICH. A primary outcome of excellent or good hemostatic efficacy at 12 h post-reversal was assessed. Secondary outcomes evaluated were change in hematoma volume size at 12 h, functional status at discharge, need for surgical intervention or additional hemostatic agents post-reversal, new thrombotic event within 28 days, 28-day all-cause mortality, discharge disposition, and hospital and intensive care unit lengths of stay. A total of 70 patients were included (4F-PCC, n = 47; AA, n = 23). For the primary outcome analysis, 21 patients were included in the 4F-PCC group and 12 in the AA group. The rate of effective hemostasis was similar between the 4F-PCC and AA groups (66.7% vs 75%, p = 0.62). There were no statistically significant differences between the groups for secondary outcomes, including 28-day mortality (40.4% vs 39.1%, p = 0.92) and thrombotic complications within 28 days of reversal (17.0% vs 21.7%, p = 0.63). In patients who experienced an ICH while taking apixaban or rivaroxaban, 4F-PCC and AA were found to have similar rates of excellent or good hemostatic efficacy.

Topics: Adult; Anticoagulants; Blood Coagulation Factors; Factor IX; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Hemostatics; Humans; Intracranial Hemorrhages; Recombinant Proteins; Retrospective Studies; Rivaroxaban; Thrombosis

Drug-specific anti-Xa concentrations can be used to assess the presence of drug effects; however, there is inadequate guidance for clinicians on the interpretation and clinical application of these results. The purpose of this study is to review patients' first apixaban and rivaroxaban anti-Xa concentrations to identify indications for monitoring and common therapeutic interventions made based on the results. In addition, we compared bleeding and thrombotic outcomes between the obesity group body mass index ≥40 kg/m 2 and the standard group body mass index 25-39.9 kg/m 2 . A retrospective analysis was conducted at a large academic medical center from January 1, 2020, to December 31, 2020. Primary outcomes were indications for anti-Xa concentrations and interventions on results. A total of 180 patients were included in the analysis, with 119 patients (66%) in the apixaban group and 61 patients (34%) in the rivaroxaban group. The most common indications for anti-Xa concentrations were extreme body weight (23%) and concern for bleeding (22%). About half of the anti-Xa concentrations resulted in therapy changes including holding for procedure, switching to heparin or enoxaparin, holding for an elevated anti-Xa concentration or concern for bleeding, adjusting direct-acting oral anticoagulant dose, or switching to an alternative oral anticoagulant. There were no differences in bleeding complications (5% [2] vs. 16% [14], P = 0.11) or thrombotic complications (8% [3] vs. 9% [8], P = 0.85) between the obesity group and the standard group. Despite the lack of validation of therapeutic ranges for anti-Xa concentrations, this study showed clinical situations where anti-Xa concentration monitoring can be of value.

Topics: Anticoagulants; Factor Xa Inhibitors; Hemorrhage; Humans; Obesity; Pyridones; Retrospective Studies; Rivaroxaban

Central venous catheters are prone to clotting, particularly in patients with cancer. Although low-molecular-weight heparin and direct oral anticoagulants, such as apixaban and rivaroxaban, have been evaluated for the prevention of catheter thrombosis, their efficacy remains uncertain.. Compare apixaban and rivaroxaban with enoxaparin for the prevention of catheter-induced clotting in vitro.. To address this uncertainty, we used a well-established microplate-based assay to compare the effects of enoxaparin, apixaban, and rivaroxaban on catheter-induced thrombosis and thrombin generation in human plasma.. Consistent with our previous findings, catheter segments shortened the clotting time and promoted thrombin generation. When compared at concentrations with similar anti-factor Xa activity as enoxaparin, apixaban and rivaroxaban were >20-fold less potent than enoxaparin for the prevention of catheter-induced clotting and thrombin generation.. The prevention of catheter thrombosis in patients with cancer is challenging. Clinical trials are needed to compare the efficacy of low-molecular-weight heparin with that of direct oral anticoagulants both for the prevention and treatment of catheter thrombosis.

Topics: Anticoagulants; Catheters; Enoxaparin; Factor Xa Inhibitors; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Pyridones; Rivaroxaban; Thrombin; Thrombosis

Safety and efficacy of direct oral anticoagulants (DOAC) in low weight patients with atrial fibrillation (AF) is unclear due to few low body weight patients enrolled in clinical trials. To assess bleeding and thrombotic event rates for patients with AF that are prescribed apixaban and have a low versus normal body weight. We analyzed patients with AF prescribed apixaban from 2017 to 2020 with at least 12 months of follow-up. Patients were divided into low [< 60 kg (kg)] and normal (60-100 kg) weight cohorts. Bleeding and thrombotic event rates were compared. Poisson regression and Cox proportional hazard models were used to estimate adjusted adverse event rates. A total of 545 patients met inclusion criteria. In the unadjusted analysis, there was an increase in non-major bleeding events requiring an Emergency Department visit more often in the low versus normal weight cohort (10.8 versus 7.4 per 100 patient-years, p = 0.15). Thrombotic event rates also occurred more often in the lower versus normal weight cohort (2.4 versus 0.9 per 100 patient-years, p = 0.09). However, adjusted analysis found no statistically significant difference in bleeding or thrombotic events between low and normal weight cohorts. The adjusted hazard ratio for bleeding was similar between the two weight cohorts. The use of apixaban in low body weight patients was not associated with higher rates of bleeding or thrombotic events, compared to those with normal body weight, after adjusting for potential confounding covariates. Larger studies may offer further insight into the overall safety and efficacy of DOAC therapy in these patients.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Hemorrhage; Humans; Ideal Body Weight; Pyridones; Rivaroxaban; Stroke; Thinness; Warfarin

Topics: Anticoagulants; Factor Xa Inhibitors; Heparin, Low-Molecular-Weight; Humans; Pyrazoles; Pyridones; Rivaroxaban

Topics: Humans; Propensity Score; Rivaroxaban

Direct oral anticoagulants (DOAC) are increasingly being prescribed for prophylaxis of thromboembolic events. Their use, particularly in emergency settings is difficult as blood level measurements are often not immediately available and until recently there was no possibility for reversal. This article presents the case of a severely injured patient with life-threatening traumatic bleeding under long-term treatment with the factor Xa inhibitor apixaban, viscoelasticity-based detection of residual systemic anticoagulatory activity and targeted reversal.. Direkte orale Antikoagulanzien (DOAK) werden zunehmend zur Prophylaxe thrombembolischer Ereignisse eingesetzt. Ihr Umgang, insbesondere in Notfallsituationen, gestaltet sich schwierig, da Spiegelmessungen oft nicht zeitnah zur Verfügung stehen und bis vor Kurzem keine Möglichkeit zur Antagonisierung bestand. Es wird die notfallmäßige Behandlung eines Schwerstmehrfachverletzten mit lebensbedrohlicher traumatischer Blutung unter Dauertherapie mit dem Faktor-Xa-Hemmer Apixaban, viskoelastizitätsbasierter Detektion gerinnungsrelevanter Restaktivität bei Schockraumaufnahme und gezielter Wirkungsaufhebung beschrieben.

Topics: Anticoagulants; Hemorrhage; Humans; Pyridones; Rivaroxaban

Topics: Anticoagulants; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Pyrazoles; Recombinant Proteins; Rivaroxaban

Amiodarone, the most effective antiarrhythmic drug in atrial fibrillation, inhibits apixaban and rivaroxaban elimination, thus possibly increasing anticoagulant-related risk for bleeding.. For patients receiving apixaban or rivaroxaban, to compare risk for bleeding-related hospitalizations during treatment with amiodarone versus flecainide or sotalol, antiarrhythmic drugs that do not inhibit these anticoagulants' elimination.. Retrospective cohort study.. U.S. Medicare beneficiaries aged 65 years or older.. Patients with atrial fibrillation began anticoagulant use between 1 January 2012 and 30 November 2018 and subsequently initiated treatment with study antiarrhythmic drugs.. Time to event for bleeding-related hospitalizations (primary outcome) and ischemic stroke, systemic embolism, and death with or without recent (past 30 days) evidence of bleeding (secondary outcomes), adjusted with propensity score overlap weighting.. There were 91 590 patients (mean age, 76.3 years; 52.5% female) initiating use of study anticoagulants and antiarrhythmic drugs, 54 977 with amiodarone and 36 613 with flecainide or sotalol. Risk for bleeding-related hospitalizations increased with amiodarone use (rate difference [RD], 17.5 events [95% CI, 12.0 to 23.0 events] per 1000 person-years; hazard ratio [HR], 1.44 [CI, 1.27 to 1.63]). Incidence of ischemic stroke or systemic embolism did not increase (RD, -2.1 events [CI, -4.7 to 0.4 events] per 1000 person-years; HR, 0.80 [CI, 0.62 to 1.03]). The risk for death with recent evidence of bleeding (RD, 9.1 events [CI, 5.8 to 12.3 events] per 1000 person-years; HR, 1.66 [CI, 1.35 to 2.03]) was greater than that for other deaths (RD, 5.6 events [CI, 0.5 to 10.6 events] per 1000 person-years; HR, 1.15 [CI, 1.00 to 1.31]) (HR comparison:. Possible residual confounding.. In this retrospective cohort study, patients aged 65 years or older with atrial fibrillation treated with amiodarone during apixaban or rivaroxaban use had greater risk for bleeding-related hospitalizations than those treated with flecainide or sotalol.. National Heart, Lung, and Blood Institute.

Topics: Aged; Amiodarone; Anti-Arrhythmia Agents; Anticoagulants; Atrial Fibrillation; Dabigatran; Embolism; Female; Flecainide; Hemorrhage; Hospitalization; Humans; Ischemic Stroke; Male; Medicare; Retrospective Studies; Rivaroxaban; Sotalol; Stroke; United States

In Bordeaux University Hospital, neurologists are required to prescribe thrombolysis using telemedicine (telethrombolysis) for anticoagulated stroke patients admitted in peripheral centers in the Nouvelle-Aquitaine region. However, due to the bleeding risk, the maximum concentration of DOAC authorizing thrombolysis is 30, 50 or 100 ng/mL (depending on the sources and the patient-specific benefit-risk ratio). Most of the time, specific assays of Direct Oral Anticoagulants (DOACs) are not available in these peripheral centers. We therefore studied an alternative test: the Unfractionated Heparin (UFH) anti-Xa activity which is available in most laboratories and could be used to estimate the DOAC concentration.. Five centers were included in our study: three centers using the Liquid Anti-Xa HemosIL® Werfen reagent and two centers using the STA-Liquid Anti-Xa® Stago reagent. For each reagent, we established correlation curves between DOAC and UFH anti-Xa activities and determinated UFH cut-offs for the thresholds of 30, 50 and 100 ng/mL respectively.. A total of 1455 plasmas were tested. There is an excellent correlation between DOAC and UFH anti-Xa activities using a third-degree modeling curve, independently the reagent used. However, a significant inter-reagent variability is observed concerning the obtained cut-offs.. Our study makes unsuitable the use of a universal cut-off. In opposition to recommendations made by other publications, the UFH cut-offs must be adapted to the reagent used locally by the laboratory, and to the considered DOAC.

Topics: Anticoagulants; Blood Coagulation Tests; Factor Xa Inhibitors; Heparin; Heparin, Low-Molecular-Weight; Humans; Pyridones; Rivaroxaban

Upper extremity deep vein thrombosis (UEDVT) may occur without inciting factor or may be secondary to malignancy, surgery, trauma, central venous catheter or related to thoracic outlet syndrome (TOS). International guidelines recommend anticoagulant treatment for at least three months, in particular the use of vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs). No data on extended anticoagulant therapy and reduced dose of DOACs have been reported in patients affected by UEDVT with persistent thrombotic risk (active cancer, major congenital thrombophilia) or without affected vein recanalization. In our retrospective observational study, including 43 patients, we treated secondary UEDVT with DOACs. In the acute phase of thrombosis (median time of 4 months), we used therapeutic dose of DOACs; the 32 patients with permanent thrombotic risk factors or without recanalization of the UEDVT were shifted to low-dose DOACs (apixaban 2.5 mg twice daily or rivaroxaban 10 mg daily). During therapy with full-dose DOACs, 1 patient presented recurrence of thrombosis; no thromboembolic events were observed during treatment with low-dose DOACs. During full-dose treatment, 3 patients presented minor hemorrhagic complications; no hemorrhagic events were observed during DOACs at low dose. We think our preliminary data could support the indication to extend the anticoagulation with dose reduction of DOACs in patients affected by UEDVT and no-transient thrombotic risk. These data should be confirmed in randomized controlled prospective study.

Topics: Administration, Oral; Anticoagulants; Hemorrhage; Humans; Prospective Studies; Rivaroxaban; Upper Extremity Deep Vein Thrombosis

Management of cancer-associated thrombosis (CAT) is usually performed employing low molecular weight heparin (LMWH) or direct oral anticoagulants (DOACs). Low-intensity DOACs are the mainstay for extended duration therapy for VTE in non-oncologic patients. The aim of our study was to evaluate the efficacy and the safety of low doses of apixaban or rivaroxaban as secondary prophylaxis in patients affected by hematological malignancies with follow-up > 12 months. We report an observational, retrospective, single-center study that evaluated consecutive patients referred to our center between January 2016 and January 2023. The DOACs were administered at full dose during the acute phase of VTE and then at low dose for the extended phase. We included 154 patients: 53 patients affected by hematological malignancies compared to 101 non-neoplastic patients. During full-dose treatment, no thrombotic recurrences were observed in the two groups. During low-dose therapy, 2 (1.9%) thrombotic events (tAE) were observed in the control group. During full-dose treatment, the rate of bleeding events (bAE) was 9/154 (5.8%): 6/53 (11%) in hematological patients and 3/101 (2.9%) in non-hematological patients (p = 0.0003). During low-dose therapy, 4/154 (2.6%) bAE were observed: 3/53 (5.5%) in the hematologic group and 1 (1%) in the control group (p = 0.07). We found encouraging data on the safety and efficacy of low doses of DOACs as secondary prophylaxis in the onco-hematologic setting; no thrombotic complications were observed, and the incidence of hemorrhagic events was low.

Topics: Fibrinolytic Agents; Hematologic Neoplasms; Heparin, Low-Molecular-Weight; Humans; Retrospective Studies; Rivaroxaban; Venous Thromboembolism

Quantification of direct oral anticoagulant (DOAC) plasma levels can guide clinical management, but insight into clinical scenarios surrounding DOAC-calibrated anti-FXa assays is limited.. Apixaban- and rivaroxaban-calibrated chromogenic anti-Xa assays performed over a 1-year period were retrospectively analyzed. Patient demographics, DOAC history, concomitant medications, and renal/liver comorbidities were obtained. Indications for testing and associated clinical actions were reviewed. Machine learning (ML) models predicting clinical actions were evaluated.. In total, 371 anti-FXa apixaban and 89 anti-FXa rivaroxaban tests were performed for 259 and 67 patients in recurring urgent (acute bleeding, unplanned procedures) and nonurgent situations, including several scenarios not captured by existing testing recommendations (eg, drug monitoring, recurrent thromboembolic events, bleeding tendency). In urgent settings, andexanet reversal was guided by radiologic and clinical findings over DOAC levels in 14 of 32 instances, while 51% of apixaban patients qualified for nonreversal strategies through the availability of levels. Levels also informed procedure/intervention timing and supported management decisions when DOAC clearance or DOAC target levels were in question. The importance of clinical context was emphasized by exploratory ML models predicting particular clinical actions.. Although clinical situations are complex, DOAC testing facilitates clinical decision-making, including reversal, justifying more widespread implementation of these assays.

Topics: Anticoagulants; Factor Xa Inhibitors; Hemorrhage; Humans; Pyridones; Retrospective Studies; Rivaroxaban

To compare the risk of readmissions for major bleeding within one year between apixaban and rivaroxaban as a component of triple antithrombotic therapy.. This study was a multicenter, retrospective cohort study conducted at two academic medical centers in the Western New York and New York City region between July 1, 2011 and September 25, 2019. Adult patients were included if they were diagnosed with atrial fibrillation or venous thromboembolism and discharged on new triple antithrombotic therapy. The primary outcome compared the rates of 1-year readmission for major bleeding between apixaban and rivaroxaban groups. Secondary outcomes included rate of ischemic outcomes. Time to event analysis was determined with a Kaplan-Meier plot and Cox proportional hazard ratios (HR).. A total of 378 patients were included in the study, 212 in the apixaban group and 166 in the rivaroxaban group. Within 1 year, readmission for major bleeding events occurred in six (2.8%) patients in the apixaban group and four (2.4%) patients in the rivaroxaban group ( P  = 1.000). After adjustment, the major bleeding event rate was not statistically significantly different between apixaban and rivaroxaban [adjusted hazard ratio (aHR) 0.68, 95% confidence interval (CI) 0.12-3.77; P  = 0.6624]. Higher albumin levels were identified to be protective against major bleeding related readmission events (aHR 0.18, 95% CI 0.05-0.63; P  = 0.0072). The ischemic outcome occurred in seven (3.3%) patients in the apixaban group and three (1.8%) in the rivaroxaban group ( P  = 0.7368).. Use of apixaban or rivaroxaban in a triple antithrombotic regimen was not associated with bleeding or ischemic outcomes.

Topics: Adult; Anticoagulants; Atrial Fibrillation; Dabigatran; Fibrinolytic Agents; Hemorrhage; Humans; Pyridones; Retrospective Studies; Rivaroxaban; Stroke

Direct oral anticoagulants (DOACs) are widely used for stroke prevention in atrial fibrillation. However, they have a bleeding complication. Breast cancer resistance protein, encoded by. Patients treated with apixaban and rivaroxaban were enrolled from June 2018 to December 2021. Five single nucleotide polymorphisms (SNPs) of. Among 293 patients, 64 were cases. The mean age of the patients was 68.8 years, and males comprised 62.5% of the study population. Model I revealed that a history of bleeding, concurrent use of proton pump inhibitor (PPI),. The modified HAS-BLED score, a history of bleeding, concurrent use of PPI,

Topics: Aged; ATP Binding Cassette Transporter, Subfamily G, Member 2; Case-Control Studies; Female; Humans; Male; Neoplasm Proteins; Polymorphism, Single Nucleotide; Rivaroxaban

Possible challenges in dosing non-vitamin K antagonist oral anticoagulants in nonvalvular atrial fibrillation (NVAF) and limited evidence in Saudi Arabia make it difficult to assess their appropriateness. This study aimed to assess the appropriateness of prescribing rivaroxaban and apixaban in hospitalized patients with newly diagnosed NVAF. This single-center, descriptive, retrospective study was conducted at a tertiary hospital in Saudi Arabia between December 2018 and December 2019. The included patients were aged 18 years and older with newly diagnosed NVAF who received either rivaroxaban or apixaban during hospitalization. The primary outcome was the dosing appropriateness of rivaroxaban and apixaban in NVAF based on recent food and drug administration prescribing guidelines. Descriptive statistics including frequencies and percentages as well as mean ± standard deviation was used to summarize the data. Pearson Chi-square was used to test for significant difference in proportions of appropriate and inappropriate dosing. Pearson Correlation was used to test for associations between underdosing and overdosing with other patients characteristics. A priori P value < .05 was considered significant throughout. A total of 203 patients were included in our analysis. Majority of the patients {125 (61.6%), P = .001} received rivaroxaban. Overall, the dosing appropriateness observed in 143 (70.5%) of the patients who received the rivaroxaban and apixaban was significantly higher than the dosing inappropriateness observed in 60 (29.5%) of the patients who received the same drugs, P < .001. Apixaban had the highest proportion of patients, 45 (57.7%) with dosing inappropriateness. Overall, underdosing was the most common dosing inappropriateness observed in 53 (26.1%) of the patients. There was a significant negative correlation between the drugs underdosing and creatinine clearance, r = -0.223, P = .001. The findings in our present study showed that majority of the patients received appropriate dosing of rivaroxaban and apixaban in hospitalized patients with NVAF. Healthcare providers should update themselves with the recent dosing recommendations for the non-vitamin K-antagonist oral anticoagulants in NVAF to further improve the dosing appropriateness in hospitalized patients with NVAF.

Topics: Anticoagulants; Atrial Fibrillation; Humans; Retrospective Studies; Rivaroxaban; Tertiary Care Centers; United States

Apixaban is a direct-acting oral anticoagulant that selectively inhibits factor Xa. Reversal strategies utilized to treat factor Xa inhibitor-associated bleeding include andexanet alfa, prothrombin complex -concentrate (PCC), and activated PCC (aPCC). The optimal treatment of traumatic intracranial hemorrhage in the setting of an apixaban overdose is unknown.. This case report describes a 69-year-old female who initially presented to an emergency department at a community hospital due to a ground-level fall with traumatic intracranial hemorrhage. The patient reportedly ingested apixaban 275 mg, carvedilol 250 mg, atorvastatin 1,200 mg, and unknown amounts of amlodipine and ethanol. Anti-inhibitor coagulant complex, an aPCC, was administered approximately 3 hours after presentation. Initial thromboelastography performed approximately 4 hours after presentation showed a prolonged reaction time of 16.8 minutes. Ongoing imaging and evidence of coagulopathy prompted repeated aPCC administration to a cumulative dose of approximately 100 U/kg. The patient underwent craniotomy with hematoma evacuation. Postoperative imaging showed expansion of the existing intracranial hemorrhage and new areas of hemorrhage. Andexanet alfa was administered approximately 18 hours after presentation, followed by repeat craniotomy with evacuation of the hematoma. No further expansion of the intracranial hemorrhage was observed, and the reaction time on thromboelastography was normalized at 6.3 minutes.. This case suggests that andexanet alfa may have a role in the management of traumatic hemorrhage in the setting of an acute massive apixaban overdose. Use of andexanet alfa, PCC, and aPCC in this context requires further research.

Topics: Aged; Anticoagulants; Drug Overdose; Factor Xa; Factor Xa Inhibitors; Female; Hematoma; Hemorrhage; Humans; Intracranial Hemorrhage, Traumatic; Intracranial Hemorrhages; Recombinant Proteins; Rivaroxaban

Andexanet alfa is a Gla-domainless FXa (GDXa) analog used as an antidote to FXa inhibitors. Despite its clinical use, laboratory monitoring for anti-Xa reversal and the effect of andexanet on fibrinolysis has not been explored. We used a GDXa with a serine-to-alanine mutation at position 195 (chymotrypsin numbering) to model the interaction between andexanet and apixaban.. Six batches of pooled plasma, and whole blood from healthy volunteers were treated with increasing concentrations of apixaban with/without GDXa. Thrombin generation and plasmin generation (TG and PG) were tested in plasma, and whole blood thrombus formation was tested using thromboelastometry or a flow-chamber system. FXa was also tested in isolation for its ability to support plasmin activation with/without apixaban and GDXa.. Apixaban (250-800 nM) concentration-dependently decreased the velocity and peak of TG in plasma. Apixaban prolonged the onset of thrombus formation in thromboelastometry and flow-chamber tests. GDXa normalized apixaban-induced delays in TG and whole blood thrombus formation. However, GDXa minimally affected the low PG velocity and peak caused by apixaban at higher concentrations (500-800 nM). FXa promoted plasmin generation independent of fibrin that was inhibited by apixaban at supratherapeutic concentrations.. This study demonstrated the feasibility of assessing coagulation lag time recovery in plasma and whole blood following in vitro apixaban reversal using GDXa, a biosimilar to andexanet. In contrast, GDXa-induced changes in plasmin generation and fibrinolysis were limited in PG and tPA-added ROTEM assays, supporting the endogenous profibrinolytic activity of FXa and its inhibition at elevated apixaban concentrations.

Topics: Blood Coagulation; Factor Xa; Factor Xa Inhibitors; Fibrinolysin; Humans; Pyridones; Rivaroxaban; Thrombosis

We previously conducted a retrospective cohort study using chart review of oral anticoagulant-naïve Japanese patients with nonvalvular atrial fibrillation (NVAF) that assessed the risk of major bleeding and stroke/systemic embolism (SE) events of apixaban versus warfarin.. In this subgroup analysis, we compared the risk of major bleeding and stroke/SE events by stratifying patients into four subgroups matched 1:1 using propensity score matching (PSM) according to baseline creatinine clearance (CrCl; mL/min): ≥ 15 to < 30, ≥ 30 to < 50, ≥ 50 to < 80, and ≥ 80.. Of the 7074 patients in the apixaban group and 4998 in the warfarin group eligible for inclusion in the analysis, 4385 were included in each group after PSM. Incidence rates of major bleeding and stroke/SE events were generally lower with apixaban versus warfarin across the CrCl subgroups. When all patients with a CrCl change of < 0 mL/min per year during the study period (apixaban, n = 3871; warfarin, n = 2635) were stratified into four subgroups based on the magnitude of CrCl decline (median CrCl change [mL/min] per year: - 1.09, - 3.48, - 7.54, and - 36.92 for apixaban, and - 1.10, - 3.65, - 7.85, and - 40.40 for warfarin), the incidence rates of major bleeding and stroke/SE events generally increased with an increasing CrCl decline per year in both groups.. In Japanese patients with NVAF, the safety and effectiveness of apixaban and warfarin were consistent across different renal subgroups, including those with severe renal impairment. Our results highlight the importance of monitoring renal function variations over time in patients with NVAF.. NCT03765242.

Topics: Anticoagulants; Atrial Fibrillation; East Asian People; Hemorrhage; Humans; Kidney; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Warfarin

The use of activated prothrombin complex concentrate (aPCC) to treat direct oral anticoagulant (DOAC)-associated bleeding is off-label and clinical experience is limited.. We aimed to assess the efficacy and safety of aPCC in reversing the anticoagulant effect of apixaban and rivaroxaban in patients presenting with major bleeding.. A retrospective cohort study of adult non-randomized patients was conducted at a tertiary referral medical center in the United States (US) to investigate the use of aPCC for the reversal of the anticoagulant effect of apixaban and rivaroxaban in patients presenting with major bleeding. The primary outcome was achieving clinical hemostasis according to prespecified criteria. Safety outcomes included the occurrence of thrombotic events during hospitalization.. A total of 217 patients were included in the study. Intracranial hemorrhage (ICH) was the most common site of bleeding (n = 100, 46.1%), followed by gastrointestinal bleed (n = 87, 40.1%). Clinical hemostasis was achieved in 170 patients (78.3%), and the risk of not achieving hemostasis with ICH-related bleeding was significantly higher than that of non-ICH-related bleeding (2.5, 95% confidence interval [CI] 1.44-4.34; p < 0.001). Eight patients not achieving hemostasis died during hospitalization, all of whom were suffering from ICH, and mortality associated with non-ICH-related bleeding was significantly lower compared with ICH-related bleeding (0.91, 95% CI 0.86-0.97; p < 0.001). Thromboembolic events during hospitalization occurred in one patient (0.5%).. The use of aPCC for the management of apixaban- or rivaroxaban-related major bleeding is effective in most cases and is associated with a low risk of thromboembolism.

Topics: Adult; Anticoagulants; Factor Xa Inhibitors; Hemorrhage; Humans; Pyridones; Retrospective Studies; Rivaroxaban; Thromboembolism

Direct oral anticoagulant (DOAC)-inhibiting factor Xa (FXa-DOAC) are being increasingly used as prophylaxis of venous thromboembolism and for prevention of stroke in patients with atrial fibrillation. In contrast to vitamin K antagonists, DOACs do not require monitoring in general. However, it is sometimes of value in the acute setting, for instance when considering a reversal agent in uncontrolled bleeding in patients on DOAC.. We evaluated if a low-molecular weight heparin (LMWH)-calibrated anti-factor Xa assay could be used to estimate FXa-DOAC concentration in the concentration range <100 ng/mL by spiking known concentrations of FXa-DOAC and from those result calculate the FXa-DOAC concentration from the response of the LMWH assay. This procedure was then evaluated by comparing the result with a drug-calibrated chromogenic assay and liquid chromatography tandem mass spectrometry (LC-MS/MS) on clinical plasma samples from patients treated with apixaban or rivaroxaban.. Although the measuring range was narrower for the LMWH-calibrated assay, concentrations recalculated from the LMWH assay was comparable with those measured by the drug-calibrated method when compared with LC-MS/MS.. We suggest that an LMWH-calibrated anti-factor Xa assay can be used after characterization of the response of FXa-DOACs to give guidance on the concentration of apixaban and rivaroxaban. Shorter turnaround time than LC-MS/MS and the greater availability than drug-calibrated chromogenic assays could make this a valuable option in the acute setting.

Topics: Atrial Fibrillation; Blood Coagulation Tests; Chromatography, Liquid; Clinical Decision-Making; Disease Management; Disease Susceptibility; Drug Monitoring; Factor Xa Inhibitors; Heparin, Low-Molecular-Weight; Humans; Pyrazoles; Pyridones; Reproducibility of Results; Rivaroxaban; Sensitivity and Specificity; Stroke; Tandem Mass Spectrometry; Venous Thromboembolism

Oral direct factor Xa inhibitors (FxaIs) are renally eliminated; thus, acute kidney injury (AKI) may increase the risk for drug accumulation and bleeding. There is minimal data describing the effects of AKI on FxaI anti-Xa levels or clinical outcomes.. To compare anti-Xa level monitoring with standard monitoring in patients who experience AKI on apixaban or rivaroxaban.. This retrospective study included patients admitted within a large hospital system from May 2016 to October 2020. Patients were included if they received apixaban or rivaroxaban prior to AKI. Patients were stratified into 1 of 2 groups: those with anti-Xa level monitoring or those who received standard monitoring. The primary outcome was major bleeding as defined by the International Society of Thrombosis and Haemostasis.. A total of 196 patients were included in the final analysis. Major bleeding occurred in 2 patients who received anti-Xa level monitoring, compared with 14 patients who received standard monitoring (2.1% vs 14%;. This is the first study to demonstrate that anti-Xa level monitoring was associated with a significant reduction in major bleeding compared with standard monitoring in patients with AKI who received apixaban or rivaroxaban. The optimal management of antithrombotic medications in patients with AKI and recent exposure to an FxaI requires further investigation.

Topics: Acute Kidney Injury; Anticoagulants; Factor Xa Inhibitors; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban

Clinical trials comparing direct oral anticoagulants (DOAC) to warfarin excluded patients with a history of bariatric surgery. The anatomic changes from bariatric procedures have several effects on drug absorption which can have serious consequences for these patients. We sought to describe real-world use of DOACs among adults that had a history of bariatric surgery or underwent a bariatric surgery while receiving a DOAC. We conducted a retrospective case series of adult patients, at a large academic medical center, who initiated any DOAC in 2016 thru 2019 and had a history of bariatric surgery or underwent a bariatric surgery while receiving a DOAC. Thrombotic and bleeding events were described using summary statistics and bleeding severity was described using the International Society on Thrombosis and Haemostasis criteria. Twenty-eight patients met the inclusion criteria of having bariatric surgery (Roux-en-Y gastric bypass, sleeve gastrectomy or gastric band) and receiving a DOAC. Twenty (71.4%) were prescribed apixaban and eight (28.6%) were prescribed rivaroxaban. Seven patients (25%) experienced at least one clinically relevant non-major bleeding event, including one patient (3.6%) that had a major bleeding event. Two patients (7.1%) had a thromboembolic event. Coagulation laboratory studies were infrequently performed at the time of the bleeding or clotting events. Among patients with a history of bariatric surgery, use of DOACs were commonly associated with clinically relevant non-major bleeding events and less commonly associated with major bleeding and thromboembolic events. Larger studies may offer further insight into the overall safety and efficacy of DOAC therapy in patients that have undergone bariatric surgery. The specific role of coagulation laboratory studies warrants further evaluation.

Topics: Administration, Oral; Adult; Anticoagulants; Atrial Fibrillation; Bariatric Surgery; Dabigatran; Hemorrhage; Humans; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Thromboembolism; Thrombosis

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Humans; Pyrazoles; Pyridones; Renal Dialysis; Rivaroxaban; Stroke

Monitoring of direct oral anticoagulants (DOACs) with calibrated anti-Xa assay is limited by the high intra- and interindividual variations of the test results. Thrombin generation (TG) is a global hemostatic assay that reflects the patient´s individual coagulation status. The aim of this study was to investigate the influence of DOACs on TG measured with a fully automated assay system.. All consecutive patients under apixaban and rivaroxaban coming to the outpatient coagulation center MVZ Limbach, Magdeburg, Germany between October 2017 and April 2020 were included. DOAC plasma levels were correlated with TG assessed using the fully automated Ceveron TG analyzer.. A total of 703 rivaroxaban and 252 apixaban containing plasma samples were included. There was a significant correlation between DOAC plasma levels and all TG parameters except for lag time regarding apixaban. Time to peak and peak thrombin followed an exponential regression curve, while this was linear for the endogenous thrombin potential (ETP). Apixaban showed a lower correlation coefficient for all TG parameters compared with rivaroxaban, and thrombin generation was less influenced by apixaban than rivaroxaban at plasma levels >100 ng/ml. The sensitivity and negative predictive value of normal TG parameters for the prediction of DOAC plasma levels <30 ng/ml was >85%.. The present data show a moderate predominantly nonlinear correlation between TG parameters and plasma levels of apixaban and rivaroxaban. Rivaroxaban has a stronger effect on TG than apixaban.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Blood Coagulation Tests; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; ROC Curve; Thrombin; Venous Thrombosis

This study established the performance characteristics of DOAC-Remove for neutralization of the effects of rivaroxaban and apixaban in lupus anticoagulant (LAC) testing.. Normal donor, LAC control, and patient samples were spiked with rivaroxaban or apixaban to simulate their effects on the dilute Russell's viper venom time (dRVVT), activated partial thromboplastin time (APTT), and dilute prothrombin time (dPT). Anti-Xa activity was measured after spiking and after DOAC-Remove neutralization. Accuracy, complex precision, and reference interval verification were evaluated.. DOAC-Remove neutralized rivaroxaban and apixaban concentrations as high as 415 ng/mL and 333 ng/mL, respectively. Percentage positive and negative agreement between the baseline and postneutralization interpretations were 75% or higher for the dRVVT and APTT methods but not for the dPT method. Coefficients of variation (CVs) were 10% or less for all assays except the Staclot-LA delta, which had a standard deviation of 2.5 seconds or CV of 25% or less depending on the level. The laboratory's reference intervals were verified for the dRVVT and APTT assays after DOAC-Remove treatment but not for the dPT assays.. DOAC-Remove appears to have acceptable performance characteristics for neutralizing the effects of rivaroxaban and apixaban in the dRVVT and APTT methods but not in the dPT method.

Topics: Administration, Oral; Anticoagulants; Blood Coagulation Tests; Humans; Lupus Coagulation Inhibitor; Partial Thromboplastin Time; Prothrombin Time; Pyrazoles; Pyridones; Rivaroxaban

Heparin-induced thrombocytopenia (HIT) is an adverse hematologic drug reaction that results in thrombocytopenia. This potentially life-threatening event is due to the administration of heparin products, such as unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH). The incidence of HIT occurs in <0.1%-7% of hospitalized patients treated with heparin products, with a risk of thrombosis as high as 50%. In 2018, the American Society of Hematology (ASH) recommended the utilization of direct oral anticoagulants (DOACs) in clinically stable patients at average bleeding risk with HIT. The objective of this study was to evaluate the prescribing patterns of rivaroxaban and apixaban for the treatment of suspected or confirmed HIT.. This was a retrospective chart review from January 2013 through October 2019 at the University of Chicago Medicine. Twelve patients were identified to have received a DOAC for suspected or confirmed HIT.. Rivaroxaban was utilized in seven (58%) patients, six of whom received argatroban prior to starting rivaroxaban. Five (71%) of these patients were started on the recommended dose of rivaroxaban for VTE. Apixaban was utilized in five (42%) patients; four patients were started on argatroban and transitioned to apixaban. One patient was started on the suggested dose of apixaban for VTE.. After starting DOACs for suspected HIT, no patients had new thrombosis during hospitalization. Eight patients (67%) followed up at our institution within 6 months of their discharge date. No subsequent thrombi formation were identified for any of these patients. The results of this study add to the expanding literature regarding the safety and efficacy of DOAC use in HIT, and indicate DOACs are being increasingly utilized for the treatment of confirmed or suspected HIT.

Topics: Adult; Aged; Arginine; Factor Xa Inhibitors; Female; Heparin; Humans; Male; Middle Aged; Pipecolic Acids; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Sulfonamides; Thrombocytopenia

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

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

The purpose of this study is to assess efficacy of 4-factor prothrombin complex concentrates (4F-PCC) for direct oral anticoagulant (DOAC)-associated intracranial hemorrhage (ICH) as compared to its use in warfarin-associated ICH. A retrospective cohort study was performed to compare the efficacy of 4F-PCC for reversal of apixaban and rivaroxaban versus warfarin for ICH at Cooper University Health Care from January 2015 to December 2019. Patients included were ≥ 18 years of age who developed an ICH while on apixaban, rivaroxaban, or warfarin. The primary outcome was to compare the percentage of patients with Excellent or Good hemostatic efficacy after 4F-PCC administration. Secondary outcomes were to describe functional outcomes at discharge, in-hospital mortality, and thrombotic complications after 4F-PCC administration. A total of 159 patients were included; 115 patients received warfarin and 44 patients received a DOAC (apixaban, n = 22; rivaroxaban, n = 22). 70 patients were evaluable for the primary endpoint. Thirty-four (66.7%) patients in the warfarin group versus 14 (73.7%) patients in the DOAC group were determined to have excellent or good hemostatic efficacy (p = 0.57). In-hospital mortality (30.4% vs. 40.9%, p = 0.21) and thrombotic complications (9.6% vs. 11.4%, p = 0.67) were comparable between the warfarin vs. DOAC groups, respectively. This small, retrospective study found no difference in patients with excellent/good hemostatic efficacy after reversal with 4F-PCC for DOAC-associated ICH compared to warfarin-associated ICH. This study is limited by its retrospective nature and sample size. Larger, prospective studies are needed to further determine the efficacy of 4F-PCC in reversing DOAC-associated ICH.

Topics: Anticoagulants; Blood Coagulation Factors; Factor IX; Hemostatics; Humans; Intracranial Hemorrhages; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Warfarin

Topics: Aged; Aged, 80 and over; Amyloidosis; Anticoagulants; Antithrombins; Atrial Fibrillation; Cardiomyopathies; Dabigatran; Factor Xa Inhibitors; Female; Heart Failure; Humans; Male; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Warfarin

Bleeding safety in relation to use of systemic fluconazole and topical azoles among patients with atrial fibrillation treated with apixaban, rivaroxaban, or dabigatran is insufficiently explored, despite clinical relevance and several reports suggesting associations.. Using nationwide Danish registers, we identified patients with atrial fibrillation initiated on apixaban, rivaroxaban, or dabigatran from 2012-2018. We investigated associations between bleeding incidents and systemic fluconazole or topical azole treatment using a case-crossover design with 30-day exposure windows and reported odds ratios (OR) with 95% confidence intervals (CI).. We included 32,340 (36%), 32,409 (36%), and 24,940 (28%) patients initiated on apixaban, rivaroxaban, and dabigatran, respectively. Patients on apixaban were older (median age: 77 years; interquartile range [IQR] 70-84) compared with rivaroxaban users (median age: 75 years; IQR 68-82) and patients on dabigatran (median age: 73 years; IQR 66-80). Apixaban users had a significantly increased risk of bleeding following exposure to systemic fluconazole: odds ratio (OR) 3.5; 95% confidence interval (CI), 1.4-10.6. No increased risk was found among rivaroxaban and dabigatran users: ORs of 0.9 (95% CI, 0.2-3.0) and 1.7 (95% CI, 0.5-5.6), respectively. As to bleeding risk pertaining to topical azole exposure among apixaban, rivaroxaban, and dabigatran users, no association was found, with corresponding ORs of 0.8 (95% CI, 0.5-1.3); 1.3 (95% CI, 0.9-2.1); and 1.2 (95% CI 0.8-1.8), respectively.. In patients with atrial fibrillation on either apixaban, rivaroxaban, or dabigatran, an association between an elevated bleeding risk and use of systemic fluconazole was found among patients on apixaban. We found no increased risk of bleeding following co-exposure to topical azoles.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Azoles; Cross-Over Studies; Dabigatran; Fluconazole; Hemorrhage; Humans; Pyrazoles; Pyridones; Rivaroxaban; Stroke

Apixaban and rivaroxaban are replacing vitamin K antagonists for the treatment of venous thromboembolism (VTE) in adults; however, head-to-head comparisons remain limited.. To assess the effectiveness and safety of apixaban compared with rivaroxaban in patients with VTE.. Retrospective new-user cohort study.. U.S.-based commercial health care insurance database from 1 January 2015 to 30 June 2020.. Adults with VTE who were newly prescribed apixaban or rivaroxaban.. The primary effectiveness outcome was recurrent VTE, a composite of deep venous thrombosis and pulmonary embolism. The primary safety outcome was a composite of gastrointestinal and intracranial bleeding.. Of 49 900 eligible patients with VTE, 18 618 were new users of apixaban and 18 618 were new users of rivaroxaban. Median follow-up was 102 days (25th, 75th percentiles: 30, 128 days) among apixaban and 105 days (25th, 75th percentiles: 30, 140 days) among rivaroxaban users. After propensity score matching, apixaban (vs. rivaroxaban) was associated with a lower rate for recurrent VTE (hazard ratio, 0.77 [95% CI, 0.69 to 0.87]) and bleeding (hazard ratio, 0.60 [CI, 0.53 to 0.69]). The absolute reduction in the probability of recurrent VTE with apixaban versus rivaroxaban was 0.006 (CI, 0.005 to 0.011) within 2 months and 0.011 (CI, 0.011 to 0.013) within 6 months of initiation. The absolute reduction in the probability of gastrointestinal and intracranial bleeding with apixaban versus rivaroxaban was 0.011 (CI, 0.010 to 0.011) within 2 months and 0.015 (CI, 0.013 to 0.015) within 6 months of initiation.. Short follow-up.. In this population-based cohort study, patients with VTE who were new users of apixaban had lower rates for recurrent VTE and bleeding than new users of rivaroxaban.. None.

Topics: Aged; Cerebral Hemorrhage; Databases, Factual; Factor Xa Inhibitors; Female; Gastrointestinal Hemorrhage; Humans; Male; Pyrazoles; Pyridones; Recurrence; Retrospective Studies; Risk Factors; Rivaroxaban; United States; Venous Thromboembolism

Direct oral anticoagulant (DOAC) use presents a challenge to all providers involved in emergency care of patients since widely accepted laboratory tests to assess the level of anticoagulation for such medications are lacking. Viscoelastic tests such as thromboelastography (TEG) tests are increasingly used throughout major trauma centers to help guide resuscitation efforts in patients presenting with trauma and/or hemorrhagic shock.. The primary outcome compared TEG parameters between emergency department trauma patients reporting DOAC therapy and known normal TEG parameter values. The secondary outcome evaluated patients who reported time of last known DOAC dose within a preferred time frame of <12 h for once daily dosing DOAC therapy or < 6 h for twice daily dosing DOAC therapy.. This single-center, retrospective cohort study assessed TEG values in patients receiving DOAC therapy and compared these to institution TEG ranges considered normal. TEG values of reaction time (R time), kinetics (K), alpha angle (AA), maximum amplitude (MA), and percent lysis in 30 min (LY30) were collected for patients reporting DOAC therapy.. 40 patients were included in this study. 19 patients reported apixaban therapy and 21 reported rivaroxaban therapy. 5 (12.5%) patients had an elevated R time and 1 (2.5%) patient had a reduced MA. All other TEG values did not suggest hypocoagulability. For the secondary outcome assessing patients reporting last known dose within the preferred time frame, only the R time was elevated in 2 (14.3%) patients. Lastly, in a subgroup analysis of patients with elevated low-molecular-weight heparin (LMWH) orAnti- Xa levels, the R time was the only parameter affected in 25% of patients.. TEG values were typically not affected by rivaroxaban or apixaban use in an emergency department trauma population suggesting that TEG is not sensitive for Xa inhibitor detection and should not be relied upon for assessing anticoagulation in such settings.

Topics: Aged; Aged, 80 and over; Blood Coagulation; Factor Xa Inhibitors; Female; Humans; Male; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Thrombelastography

Based on previous large-scale in silico screening several factor Xa inhibitors were proposed to potentially inhibit SARS-CoV-2 Mpro. In addition to their known anticoagulants activity this potential inhibition could have an additional therapeutic effect on patients with COVID-19 disease. In this study we examined the binding of the Apixaban, Betrixaban and Rivaroxaban to the SARS-CoV-2 Mpro with the use of the MicroScale Thermophoresis technique. Our results indicate that the experimentally measured binding affinity is weak and the therapeutic effect due to the SARS-CoV-2 Mpro inhibition is rather negligible.

Topics: Benzamides; Binding Sites; Coronavirus M Proteins; COVID-19; COVID-19 Drug Treatment; Factor Xa Inhibitors; Humans; Molecular Dynamics Simulation; Protein Binding; Protein Stability; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; SARS-CoV-2

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Heart-Assist Devices; Humans; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Warfarin

Topics: Anticoagulants; Dabigatran; Delivery of Health Care; Humans; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke

Direct oral anticoagulants (DOACs) are now an option in the prevention and treatment of venous thromboembolic events (VTE) in patients with active cancer. Pharmacokinetics of DOACs are largely influenced by efflux transporters derived from ABC transporters, notably by P-glycoprotein (P-gp). The aim of this study was to assess the potential P-gp-mediated drug-drug interactions between 11 tyrosine kinase inhibitors (TKIs) with apixaban and rivaroxaban. Bidirectional permeabilities of apixaban and rivaroxaban were investigated across MDCK-MDR1 models, to determine half maximal inhibitory concentration (IC

Topics: Administration, Oral; Anticoagulants; ATP Binding Cassette Transporter, Subfamily B, Member 1; Axitinib; Crizotinib; Dabigatran; Drug Interactions; Humans; Imatinib Mesylate; Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyridones; Rivaroxaban

There is limited information directly comparing andexanet alfa (AA) versus four-factor prothrombin complex concentrate (4F-PCC) in intracranial hemorrhage (ICH) on apixaban or rivaroxaban.. The objective of this study was to compare the effectiveness and safety of AA versus 4F-PCC in ICH on apixaban or rivaroxaban.. This retrospective, matched, cohort analysis was conducted at a single healthcare system. Patients were matched based on baseline ICH volume. The primary outcome was good or excellent ICH hemostasis, which was defined as a 35% or less increase in ICH volume within 24 h following AA or 4F-PCC administration. The secondary outcome was thrombotic events within 14 days following AA or 4F-PCC administration.. In total, 26 AA and 26 4F-PCC patients were included in this matched cohort analysis. Both groups had comparable rates of good or excellent ICH hemostasis (AA: 92.3% vs. 4F-PCC: 88.5%, p = 1.000). Thrombotic events within 14-days were not significantly different (AA: 26.9% vs. 4F-PCC: 11.5%, p = 0.159).. This study found no significant differences in good or excellent ICH hemostasis within 24-h or new thrombotic events within 14-days in a cohort given AA or 4F-PCC for ICH while on apixaban or rivaroxaban. However, this single-center analysis is underpowered due to sample size constraints, therefore further high-quality research comparing AA safety and effectiveness versus 4F-PCC is needed.

Topics: Anticoagulants; Blood Coagulation Factors; Cohort Studies; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Intracranial Hemorrhages; Pyrazoles; Pyridones; Recombinant Proteins; Retrospective Studies; Rivaroxaban

Existing research recommends either andexanet alfa (AA) or four-factor prothrombin complex concentrate (4F-PCC) as an antidote for major bleeding events due to apixaban or rivaroxaban. Currently, there is limited published research that directly compares the risks and benefits of the two agents in patients with oral factor Xa inhibitor related traumatic and spontaneous intracerebral hemorrhages. Additional head-to-head data is needed to support favoring either AA or 4F-PCC when it comes to efficacy, safety, and cost.. A retrospective chart review was conducted to assess patients admitted to a multi-center healthcare system and a stand-alone teaching hospital in central Florida from June 2016 to December 2020. Patients included in the study were at least 18 years of age, taking apixaban or rivaroxaban prior to admission, had radiographical evidence of an intracranial hemorrhage, and received either AA or 4F-PCC as a reversal agent. The primary outcome analyzed was the level of excellent hemostasis achieved, based on a standardized rating system for effective hemostasis defined by the International Society of Thrombosis and Hemostasis (ISTH), after administration of AA or 4F-PCC. Secondary outcomes analyzed included changes in the initial hemorrhage volume as reported on computed tomography (CT) scan and at 12 to 24 h post treatment, rate of thromboembolic events, rate of inpatient mortality, and total cost of treatment after AA or 4F-PCC administration.. A total of 109 patients were included in the study with 47 in the AA group (43.1%) and 62 in the 4F-PCC group (56.9%). There were no statistically significant differences between AA and 4F-PCC in terms of the primary and secondary outcomes with the exception of total cost of treatment. The level of excellent hemostasis achieved after reversal administration of AA was seen in 27 patients (71.1%) and 41 patients (70.7%) after 4F-PCC administration (p = 1, p adjusted = 0.654 after controlling for age, ICH score, regional mass effect, and midline shift). There was no statistically significant difference in the median percentage change in hemorrhagic volume from baseline to 12-24 h after reversal treatment (0 [-0.17--0.24] vs. 0 [-0.021-0.29], p = 0.439, adjusted p = 0.601) in the AA and 4F-PCC groups, respectively. The total incidence of thromboembolic events (4 [8.5%] vs. 6 [9.7%], p = 1, adjusted p = 0.973) and rate of inpatient mortality was similar between the two groups (16 [34.0%] vs. 13 [21.0%], p = 0.134, adjusted p = 0.283). A statistically significant difference was observed with the total cost of reversal treatment: $23,602 for treatment with AA and $6692 for treatment with 4F-PCC.. No statistically significant differences were identified in primary or secondary outcomes between the two agents with the exception of total treatment cost. There is insufficient evidence based on this study to recommend AA over 4F-PCC for patients with intracranial hemorrhages associated with the use of apixaban or rivaroxaban.

Topics: Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Factor Xa; Factor Xa Inhibitors; Humans; Intracranial Hemorrhages; Pyrazoles; Pyridones; Recombinant Proteins; Retrospective Studies; Rivaroxaban; Thromboembolism

Guidelines for managing venous thromboembolism (VTE) recommend at least 90 days of therapy with oral anticoagulants. Limited evidence exists about the optimal drug for continuing therapy beyond 90 days.. To compare having prescriptions dispensed for apixaban, rivaroxaban, or warfarin after an initial 90 days of anticoagulation therapy for the outcomes of hospitalization for recurrent VTE, major bleeding, and death.. This exploratory retrospective cohort study used data from fee-for-service Medicare (2009-2017) and from 2 commercial health insurance (2004-2018) databases and included 64 642 adults who initiated oral anticoagulation following hospitalization discharge for VTE and continued treatment beyond 90 days.. Apixaban, rivaroxaban, or warfarin prescribed after an initial 90-day treatment for VTE.. Primary outcomes included hospitalization for recurrent VTE and hospitalization for major bleeding. Analyses were adjusted using propensity score weighting. Patients were followed up from the end of the initial 90-day treatment episode until treatment cessation, outcome, death, disenrollment, or end of available data. Weighted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs.. The study included 9167 patients prescribed apixaban (mean [SD] age, 71 [14] years; 5491 [59.9%] women), 12 468 patients prescribed rivaroxaban (mean [SD] age, 69 [14] years; 7067 [56.7%] women), and 43 007 patients prescribed warfarin (mean [SD] age, 70 [15] years; 25 404 [59.1%] women). The median (IQR) follow-up was 109 (59-228) days for recurrent VTE and 108 (58-226) days for major bleeding outcome. After propensity score weighting, the incidence rate of hospitalization for recurrent VTE was significantly lower for apixaban compared with warfarin (9.8 vs 13.5 per 1000 person-years; HR, 0.69 [95% CI, 0.49-0.99]), but the incidence rates were not significantly different between apixaban and rivaroxaban (9.8 vs 11.6 per 1000 person-years; HR, 0.80 [95% CI, 0.53-1.19]) or rivaroxaban and warfarin (HR, 0.87 [95% CI, 0.65-1.16]). Rates of hospitalization for major bleeding were 44.4 per 1000 person-years for apixaban, 50.0 per 1000 person-years for rivaroxaban, and 47.1 per 1000 person-years for warfarin, yielding HRs of 0.92 (95% CI, 0.78-1.09) for apixaban vs warfarin, 0.86 (95% CI, 0.71-1.04) for apixaban vs rivaroxaban, and 1.07 (95% CI, 0.93-1.24) for rivaroxaban vs warfarin.. In this exploratory analysis of patients prescribed extended-duration oral anticoagulation therapy after hospitalization for VTE, prescription dispenses for apixaban beyond 90 days, compared with warfarin beyond 90 days, were significantly associated with a modestly lower rate of hospitalization for recurrent VTE, but no significant difference in rate of hospitalization for major bleeding. There were no significant differences for comparisons of apixaban vs rivaroxaban or rivaroxaban vs warfarin.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Cohort Studies; Female; Hospitalization; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Recurrence; Retrospective Studies; Rivaroxaban; Time Factors; Venous Thromboembolism; Warfarin

 To evaluate the effectiveness and safety of apixaban versus rivaroxaban among patients with nonvalvular atrial fibrillation (NVAF) and type 2 diabetes mellitus (T2DM)..  Using the United Kingdom's Clinical Practice Research Datalink linked to the Hospital Episode Statistics repository, and the Office for National Statistics database, we identified a cohort of patients with NVAF and T2DM newly treated with apixaban or rivaroxaban between 2013 and 2020. Propensity scores with standardized mortality ratio weighting were used to control for confounding. We used weighted Cox proportional hazards models to estimate separately the hazard ratios (HRs) with 95% confidence intervals (CIs) of ischemic stroke, major bleeding, and major adverse limb events associated with the use of apixaban compared with rivaroxaban. We also evaluated whether the risk was modified by age, sex, duration of diabetes, microvascular and macrovascular complications of diabetes, nephropathy, CHA.  The cohort included 11,561 apixaban and 8,265 rivaroxaban users. Apixaban was associated with a similar risk of stroke (HR: 0.99, 95% CI: 0.79-1.23), and a 32% reduced risk of major bleeding (HR: 0.68, 95% CI: 0.59-0.78), compared with rivaroxaban. The risk of major adverse limb events was similar between apixaban and rivaroxaban (HR: 0.75, 95% CI: 0.54-1.04). Overall, the risk of ischemic stroke and major bleeding was consistent in stratified analyses..  Among patients with NVAF and T2DM, apixaban was associated with a similar risk of stroke and a lower risk of major bleeding compared with rivaroxaban.

Topics: Anticoagulants; Atrial Fibrillation; Diabetes Mellitus, Type 2; Hemorrhage; Humans; Ischemic Stroke; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke

Topics: Anticoagulants; Atrial Fibrillation; Dabigatran; Fibrinolytic Agents; Hemorrhage; Humans; Ischemia; Pyrazoles; Pyridones; Rivaroxaban; Stroke

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

The oral factor Xa inhibitors (OFXAi) apixaban and rivaroxaban are increasingly utilized for the treatment of venous thromboembolism (VTE) with recommended initial higher dose 7- and 21-day lead-in regimens, respectively. In patients receiving initial parenteral anticoagulation, it remains unknown if the full recommended higher dose OFXAi lead-in regimens are warranted, or if days can be subtracted. We aimed to describe when clinicians may deviate from recommended lead-in durations and evaluate clinical outcomes in these scenarios. This is a retrospective, observational study of patients 18 years or older who were treated with rivaroxaban or apixaban for acute pulmonary embolism (PE) or symptomatic proximal deep vein thrombosis (DVT) that received parenteral anticoagulation for at least 24 h before transitioning to the OFXAi. Among our cohort of 171 patients with acute VTE who received parenteral anticoagulation for a median of 48 h, 134 (78%) were prescribed a full OFXAi lead-in and 37 (22%) were prescribed a reduced lead-in. Patients in the reduced lead-in group were older with more cardiac comorbidities and antiplatelet use. There were four recurrent thromboembolic events within 3 months, two in the reduced lead-in group and two in the full lead-in group (5% vs. 2%, p = 0.206). Bleeding within 3 months occurred in 9 (5%) patients, with 6 events occurring in the reduced lead-in group and 3 events in the full lead-in group (16% vs. 2%, p = 0.004). Prescribing patterns of OFXAi lead-in therapy duration are variable in patients receiving initial parenteral anticoagulation. Larger cohorts are needed to better define the safety and efficacy of lead-in reduction.

Topics: Anticoagulants; Factor Xa Inhibitors; Humans; Pulmonary Embolism; Pyrazoles; Pyridones; Rivaroxaban; Venous Thromboembolism

Topics: Administration, Oral; Anticoagulants; Blood Coagulation Tests; Factor Xa Inhibitors; Heparin, Low-Molecular-Weight; Humans; Pyrazoles; Pyridones; Rivaroxaban

To investigate effects of appropriately and inappropriately dosed apixaban/rivaroxaban versus warfarin on effectiveness and safety outcomes in patients with non-valvular atrial fibrillation (NVAF).. Cohort study with nested case-control analyses using primary care electronic health records (IQVIA Medical Research Data UK database).. UK primary care.. Patients aged ≥18 years with NVAF newly prescribed apixaban (N=14 701), rivaroxaban (N=14 288) or warfarin (N=16 175) between 1 January 2012 and 30 June 2018, and followed up to 31 December 2018.. Incident cases of ischaemic stroke/systemic embolism (IS/SE) and intracranial bleeding (ICB). Cases were matched to controls on age, sex and OAC naïve status. Using logistic regression, adjusted ORs with 95% CIs were calculated for the outcomes comparing apixaban/rivaroxaban use (appropriate or inappropriate dosing based on the product label criteria) and warfarin.. For IS/SE, ORs (95% CIs) for apixaban versus warfarin were 1.19 (0.92-1.52) for appropriate dose and 1.01 (0.67-1.51) for inappropriate dose; for rivaroxaban versus warfarin, estimates were 1.07 (0.83-1.37) for appropriate dose and 1.21 (0.78-1.88) for inappropriate dose. For ICB, ORs (95% CIs) for apixaban versus warfarin were 0.67 (0.44-1.00) for appropriate dose and 0.45 (0.21-0.95) for inappropriate dose; for rivaroxaban versus warfarin, estimates were 0.81 (0.55-1.20) for appropriate dose and 1.14 (0.56-2.31) for inappropriate dose.. Dosing appropriateness in NVAF was not associated with a significant difference in IS/SE risk or increase in ICB risk versus warfarin. These findings may reflect residual confounding and biases that were difficult to control, as also seen in other observational studies. They should, therefore, be interpreted with caution, and prescribers should adhere to the dosing instructions in the respective Summary of Product Characteristics. Further studies on this topic from real-world populations are needed.

Topics: Adolescent; Adult; Anticoagulants; Atrial Fibrillation; Case-Control Studies; Cohort Studies; Embolism; Humans; Intracranial Hemorrhages; Ischemic Stroke; Primary Health Care; Pyrazoles; Pyridones; Rivaroxaban; United Kingdom; Warfarin

Andexanet alfa is approved (FDA "accelerated approval"; EMA "conditional approval") as the first specific reversal agent for factor Xa (FXa) inhibitor-associated uncontrolled or life-threatening bleeding. Four-factor prothrombin complex concentrates (4F-PCC) are commonly used as an off-label, non-specific, factor replacement approach to manage FXa inhibitor-associated life-threatening bleeding. We evaluated the effectiveness and safety of andexanet alfa versus 4F-PCC for management of apixaban- or rivaroxaban-associated intracranial hemorrhage (ICH).. This two-cohort comparison study included andexanet alfa patients enrolled at US hospitals from 4/2015 to 3/2020 in the prospective, single-arm ANNEXA-4 study and a synthetic control arm of 4F-PCC patients admitted within a US healthcare system from 12/2016 to 8/2020. Adults with radiographically confirmed ICH who took their last dose of apixaban or rivaroxaban < 24 h prior to the bleed were included. Patients with a Glasgow Coma Scale (GCS) score < 7, hematoma volume > 60 mL, or planned surgery within 12 h were excluded. Outcomes were hemostatic effectiveness from index to repeat scan, mortality within 30 days, and thrombotic events within five days. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using propensity score-overlap weighted logistic regression.. The study included 107 andexanet alfa (96.6% low dose) and 95 4F-PCC patients (79.3% receiving a 25 unit/kg dose). After propensity score-overlap weighting, mean age was 79 years, GCS was 14, time from initial scan to reversal initiation was 2.3 h, and time from reversal to repeat scan was 12.2 h in both arms. Atrial fibrillation was present in 86% of patients. Most ICHs were single compartment (78%), trauma-related (61%), and involved the intracerebral and/or intraventricular space(s) (53%). ICH size was ≥ 10 mL in volume (intracerebral and/or ventricular) or ≥ 10 mm in thickness (subdural or subarachnoid) in 22% of patients and infratentorial in 15%. Andexanet alfa was associated with greater odds of achieving hemostatic effectiveness (85.8% vs. 68.1%; OR 2.73; 95% CI 1.16-6.42) and decreased odds of mortality (7.9% vs. 19.6%; OR 0.36; 95% CI 0.13-0.98) versus 4F-PCC. Two thrombotic events occurred with andexanet alfa and none with 4F-PCC.. In this indirect comparison of patients with an apixaban- or rivaroxaban-associated ICH, andexanet alfa was associated with better hemostatic effectiveness and improved survival compared to 4F-PCC. Trial registration NCT02329327; registration date: December 31, 2014.

Topics: Adult; Aged; Anticoagulants; Blood Coagulation Factors; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Hemostatics; Humans; Intracranial Hemorrhages; Propensity Score; Prospective Studies; Pyrazoles; Pyridones; Recombinant Proteins; Retrospective Studies; Rivaroxaban; Thrombosis

Topics: Administration, Oral; Anticoagulants; Embolism; Factor Xa Inhibitors; Humans; Obesity; Pyrazoles; Pyridones; Rivaroxaban; Venous Thromboembolism; Venous Thrombosis

Although several studies have compared the effectiveness and safety of rivaroxaban and apixaban in patients with venous thromboembolism (VTE), direct comparison of these drugs with edoxaban is lacking.. We compared the effectiveness and safety of edoxaban, rivaroxaban, and apixaban in patients with VTE.. In this retrospective cohort study using a Japanese hospital administrative database, we identified three mutually exclusive groups of patients with VTE beginning treatment with edoxaban, rivaroxaban, or apixaban. Primary effectiveness outcome was recurrent VTE, and principal safety outcome was a composite of intracranial hemorrhage and gastrointestinal bleeding. Subjects were followed for up to 180 days. Baseline characteristics among groups were balanced using propensity score matching weights.. Three thousand three hundred sixty-nine edoxaban, 1592 rivaroxaban, and 1998 apixaban initiators were identified. There were no significant differences among the three drugs in the prevention of recurrent VTE (adjusted incidence rate ratio [aIRR], 0.77; 95% confidence interval [CI], 0.45-1.30 for edoxaban vs. rivaroxaban; aIRR, 0.92; 95% CI, 0.54-1.56 for edoxaban vs. apixaban; and aIRR, 1.20; 95% CI, 0.69-2.10 for rivaroxaban vs. apixaban), or in the risk of intracranial hemorrhage or gastrointestinal bleeding (aIRR, 1.57, 95% CI, 0.85-2.90 for edoxaban vs. rivaroxaban; aIRR, 1.30, 95% CI, 0.76-2.23 for edoxaban vs. apixaban; and aIRR, 0.83, 95% CI, 0.42-1.64 for rivaroxaban vs. apixaban).. In routine care, edoxaban, rivaroxaban, and apixaban appear to have similar effectiveness and safety in the treatment of VTE.

Topics: Anticoagulants; Cohort Studies; Gastrointestinal Hemorrhage; Humans; Intracranial Hemorrhages; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Rivaroxaban; Thiazoles; Venous Thromboembolism

The concurrent administration of dronedarone and oral anti-coagulants is common because both are used in managing atrial fibrillation (AF). Dronedarone is a moderate inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme and P-glycoprotein (P-gp). Apixaban and rivaroxaban are P-gp and CYP3A4 substrates. This study aims to investigate the impact of exposure and bleeding risk of apixaban or rivaroxaban when co-administered with dronedarone using physiologically based pharmacokinetic/pharmacodynamic analysis.. Modeling and simulation were conducted using Simcyp® Simulator. The parameters required for dronedarone modeling were collected from the literature. The developed dronedarone physiologically based pharmacokinetic (PBPK) model was verified using reported drug-drug interactions (DDIs) between dronedarone and CYP3A4 and P-gp substrates. The model was applied to evaluate the DDI potential of dronedarone on the exposure of apixaban 5 mg every 12 h or rivaroxaban 20 mg every 24 h in geriatric and renally impaired populations. DDIs precipitating major bleeding risks were assessed using exposure-response analyses derived from literature.. The model accurately described the pharmacokinetics of orally administered dronedarone in healthy subjects and accurately predicted DDIs between dronedarone and four CYP3A4 and P-gp substrates with fold errors <1.5. Dronedarone co-administration led to a 1.29 (90 % confidence interval (CI): 1.14-1.50) to 1.31 (90 % CI: 1.12-1.46)-fold increase in the area under concentration-time curve for rivaroxaban and 1.33 (90 % CI: 1.15-1.68) to 1.46 (90 % CI: 1.24-1.92)-fold increase for apixaban. The PD model indicated that dronedarone co-administration might potentiate the mean major bleeding risk of apixaban with a 1.45 to 1.95-fold increase. However, the mean major bleeding risk of rivaroxaban was increased by <1.5-fold in patients with normal or impaired renal function.. Dronedarone co-administration increased the exposure of rivaroxaban and apixaban and might potentiate major bleeding risks. Reduced apixaban and rivaroxaban dosing regimens are recommended when dronedarone is co-administered to patients with AF.

Topics: Aged; ATP Binding Cassette Transporter, Subfamily B, Member 1; Atrial Fibrillation; Cytochrome P-450 CYP3A; Dronedarone; Drug Interactions; Hemorrhage; Humans; Pyrazoles; Pyridones; Rivaroxaban

To provide an updated comparison of the risk and cost of stroke/systemic embolism (SE) and major bleeding between direct oral anticoagulants (DOAC: apixaban, rivaroxaban, dabigatran) and warfarin among non-valvular atrial fibrillation (NVAF) patients.. Of the 264,479 eligible patients, 38,740 apixaban-warfarin pairs, 76,677 rivaroxaban-warfarin pairs, and 20,955 dabigatran-warfarin pairs were matched. Apixaban (Hazard Ratio [HR] = 0.46; 95% Confidence Interval [CI] 0.38-0.56) and rivaroxaban (HR = 0.71; 95% CI 0.63-0.80) were associated with a significantly lower risk of stroke/SE compared to warfarin. Apixaban (HR = 0.57; 95% CI 0.51-0.63) and dabigatran (HR = 0.80; 95% CI 0.70-0.90) were associated with a significantly lower risk of major bleeding; rivaroxaban (HR = 1.14; 95% CI 1.07-1.21) was associated with a significantly higher risk of major bleeding compared to warfarin. Compared to warfarin, apixaban and rivaroxaban had significantly lower stroke/SE-related medical costs; and apixaban and dabigatran had significantly lower major bleeding-related medical costs.. This real-world analysis showed DOACs to be associated with a lower risk of stroke/SE and major bleeding, and lower medical costs compared to warfarin. Among them, only apixaban appears to be associated with a significantly lower risk of all three outcomes collectively: stroke/SE, major bleeding, and lower related medical costs compared to warfarin.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Embolism; Hemorrhage; Humans; Medicare; Pyridones; Rivaroxaban; Stroke; United States; Warfarin

Outcomes following andexanet alfa reversal of factor Xa inhibitors in patients requiring urgent or emergent invasive procedures are lacking. This study aimed to describe efficacy and safety outcomes following andexanet alfa administration within 24 h of an invasive procedure.. This single-center, observational, retrospective study included patients who received andexanet alfa within 24 h of an invasive or surgical procedure. The primary outcome was hemostatic efficacy graded as excellent, good, or poor using similar definitions to the ANNEXA-4 criteria. Secondary outcomes included hospital discharge disposition, intensive care unit (ICU) and hospital length of stay, 30-day mortality, 30-day thromboischemic event rates, and serum coagulation assay changes pre- and postreversal.. Forty-four patients met inclusion criteria; of these, 27 (62.8%) received apixaban and 16 (37.2%) were treated with rivaroxaban prior to admission. The indications for reversal were categorized as intracranial (n = 20 [45.5%]) or extracranial (n = 24 [54.5%]) sites. Majority of patients required emergent operative procedures (18 [40.9%]), followed by invasive device placement (10 [22.7%]) or arterial embolization (9 [20.5%]). Thirty-eight (86.4%) patients were able to be adequately graded for hemostatic efficacy. Overall, 30 (78.9%) patients achieved excellent or good hemostasis within 24 h after periprocedural administration of andexanet alfa (19 [82.6%] apixaban vs. 11 [78.6%] rivaroxaban; 12 [80.0%] intracranial events vs. 18 [78.3%] extracranial events). Discharge disposition was most often to a short- or long-term care facilities (27 [61.4%]). Thirty-day mortality and thromboischemic complications occurred in 15 (34.1%) and 12 (27.3%) patients, respectively. Prothrombin time and antifactor Xa assay results were significantly decreased after andexanet alfa administration (p < 0.05) while thromboelastogram assay values (reaction time, kinetic time, and activated clotting time) showed nonsignificant changes pre- versus postreversal.. Andexanet alfa may be used for urgent or emergent reversal of apixaban and rivaroxaban peri-procedurally with promising hemostatic outcomes. Further prospective, comparative clinical research is warranted.

Topics: Factor Xa; Factor Xa Inhibitors; Hemorrhage; Hemostatics; Humans; Pyrazoles; Pyridones; Recombinant Proteins; Retrospective Studies; Rivaroxaban

To compare real-world effectiveness and safety of direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation (AFib) for prevention of stroke.. A comparative cohort study in UK general practice data from The Health Improvement Network database.. Before matching, 5655 patients ≥18 years with nonvalvular AFib who initiated at least one DOAC between 1 July 2014 and 31 December 2020 were included. DOACs of interest included apixaban, rivaroxaban, edoxaban and dabigatran, with the primary comparison between apixaban and rivaroxaban. Initiators of DOACs were defined as new users with no record of prescription for any DOAC during 12 months before index date.. The primary outcome was stroke (ischaemic or haemorrhagic). Secondary outcomes included the occurrence of all-cause mortality, myocardial infarction (MI), transient ischaemic attacks (TIA), major bleeding events and a composite angina/MI/stroke (AMS) endpoint.. Compared with rivaroxaban, patients initiating apixaban showed similar rates of stroke (HR: 0.93; 95% CI 0.64 to 1.34), all-cause mortality (HR: 1.03; 95% CI 0.87 to 1.22), MI (HR: 0.95; 95% CI 0.54 to 1.68), TIA (HR: 1.03; 95% CI 0.61 to 1.72) and AMS (HR: 0.96; 95% CI 0.72 to 1.27). Apixaban initiators showed lower rates of major bleeding events (HR: 0.60; 95% CI 0.47 to 0.75).. Among patients with nonvalvular AFib, apixaban was as effective as rivaroxaban in reducing rate of stroke and safer in terms of major bleeding episodes. This head-to-head comparison supports conclusions drawn from indirect comparisons of DOAC trials against warfarin and demonstrates the potential for real-world evidence to fill evidence gaps and reduce uncertainty in both health technology assessment decision-making and clinical guideline development.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Cohort Studies; Dabigatran; Hemorrhage; Humans; Ischemic Attack, Transient; Myocardial Infarction; Primary Health Care; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; United Kingdom; Warfarin

Current guidelines recommend using direct oral anticoagulants (DOACs) over warfarin in patients with atrial fibrillation (AF), but head-to-head trial data do not exist to guide the choice of DOAC.. To do a large-scale comparison between all DOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) in routine clinical practice.. Multinational population-based cohort study.. Five standardized electronic health care databases, which covered 221 million people in France, Germany, the United Kingdom, and the United States.. Patients who were newly diagnosed with AF from 2010 through 2019 and received a new DOAC prescription.. Database-specific hazard ratios (HRs) of ischemic stroke or systemic embolism, intracranial hemorrhage (ICH), gastrointestinal bleeding (GIB), and all-cause mortality between DOACs were estimated using a Cox regression model stratified by propensity score and pooled using a random-effects model.. A total of 527 226 new DOAC users met the inclusion criteria (apixaban,. Residual confounding is possible.. Among patients with AF, apixaban use was associated with lower risk for GIB and similar rates of ischemic stroke or systemic embolism, ICH, and all-cause mortality compared with dabigatran, edoxaban, and rivaroxaban. This finding was consistent for patients aged 80 years or older and those with chronic kidney disease, who are often underrepresented in clinical trials.. None.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Clinical Trials as Topic; Cohort Studies; Dabigatran; Embolism; Humans; Ischemic Stroke; Renal Insufficiency, Chronic; Rivaroxaban; United States

This study aims to analyze the real-life data of patients who were prescribed rivaroxaban and apixaban and to emphasize the points that we think will make a difference compared to randomized controlled studies.. The patients who accepted to participate in the study in whom rivaroxaban (15-20 mg) and apixaban (2.5-5 mg) were started with the diagnosis of atrial fibrillation between 01 January 2018 and 31 December 2019 and whose records were fully accessed through the hospital automation system were included in the study.. One hundred and ninety-four (48.5%) of a total of 400 patients using rivaroxaban and apixaban were women. The mean age was 73.34 ± 10.45 years, and the age range was 41-98. There was no significant difference in terms of demographic characteristics, background information of the patients, and the medications. Drug-induced complications and mortality rates were also similar. The GFR change rates of the patients in both groups were similar even though the initial GFRs were significantly higher in rivaroxaban group. The mean age and ejection fractions of the patients using rivaroxaban 15 mg were found to be lower than those of patients using rivaroxaban 20 mg whereas the mean systolic blood pressure and HAS-BLED score were found to be higher. Ischemic stroke and mortality rates were higher in patients using 15 mg rivaroxaban than patients using 20 mg rivaroxaban. The rates of nonmajor bleeding in patients using rivaroxaban 15 mg were lower compared to those using 20 mg, and this difference was statistically significant.. Stroke rates were found to be higher and to have similar bleeding rates compared to major clinical studies in our real-life analysis. However, high ischemic cerebrovascular event and low nonmajor bleeding rates are remarkable in low dose use of rivaroxaban. It is clear that there is a need to consider existing dose reduction criteria in terms of correct prescribing.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Female; Hemorrhage; Humans; Male; Middle Aged; Pyridones; Retrospective Studies; Rivaroxaban; Stroke

The advantages of direct oral anticoagulants (DOACs) over warfarin are well established in atrial fibrillation (AF) patients, however, studies that can guide the selection between different DOACs are limited. The aim was to compare the clinical outcomes of treatment with apixaban, rivaroxaban, and dabigatran in patients with AF.. We conducted a retrospective, nationwide, propensity score-matched-based observational study from Clalit Health Services. Data from 141 992 individuals with AF was used to emulate a target trial for head-to-head comparison of DOACs therapy. Three-matched cohorts of patients assigned to DOACs, from January-2014 through January-2020, were created. One-to-one propensity score matching was performed. Efficacy/safety outcomes were compared using KaplanMeier survival estimates and Cox proportional hazards models. The trial included 56 553 patients (apixaban, n = 35 101; rivaroxaban, n = 15 682; dabigatran, n = 5 770). Mortality and ischaemic stroke rates in patients treated with rivaroxaban were lower compared with apixaban (HR,0.88; 95% CI,0.78-0.99; P,0.037 and HR 0.92; 95% CI,0.86-0.99; P,0.024, respectively). No significant differences in the rates of myocardial infarction, systemic embolism, and overall bleeding were noticed between the different DOACs groups. Patients treated with rivaroxaban demonstrated lower rate of intracranial haemorrhage compared with apixaban (HR,0.86; 95% CI,0.74-1.0; P,0.044). The rate of gastrointestinal bleeding in patients treated with rivaroxaban was higher compared with apixaban (HR, 1.22; 95% CI,1.01-1.44; P, 0.016).. We demonstrated significant differences in outcomes between the three studied DOACs. The results emphasize the need for randomized controlled trials that will compare rivaroxaban, apixaban, and dabigatran in order to better guide the selection among them.

Topics: Anticoagulants; Atrial Fibrillation; Brain Ischemia; Dabigatran; Gastrointestinal Hemorrhage; Humans; Retrospective Studies; Rivaroxaban; Stroke

Low-dose direct oral anticoagulant (DOAC) use is quite prevalent in clinical practice, but evidence of its effectiveness and safety compared with high-dose DOAC in patients with atrial fibrillation (AF) remains limited. We aimed to assess the effectiveness and safety of low-dose and high-dose DOACs in patients with AF with similar baseline characteristics.. We used a cohort of hospitalized patients with a primary or secondary diagnosis of AF after discharge to the community, whose data were stored in the Quebec administrative databases, from 2011 to 2017. Older adults with AF newly prescribed with rivaroxaban (15 or 20 mg) or apixaban (2.5 mg or 5 mg) were classified as under treatment (UT) and intent to treat (ITT). We used an inverse probability treatment weighting study of new users of rivaroxaban and apixaban to address confounding by indication. The primary effectiveness outcome was ischemic stroke/systemic embolism (SE), while the primary safety outcome was major bleeding (MB). We used Cox proportional models to estimate the marginal hazard ratios (HRs).. A total of 1,722 and 4,639 patients used low-dose and standard-dose rivaroxaban, respectively, while 3,833 and 6,773 patients used low-dose and standard-dose apixaban, respectively. No significant difference was observed in the incidence of comparative stroke/SE and MB between low-dose and standard-dose rivaroxaban, except for the risk of acute myocardial infarction (AMI), which was increased with the low dose in the UT analysis. For apixaban, no difference was found in the bleeding rates, but the risk of stroke/SE (HR: 1.95; 95% confidence interval (CI): 1.38-2.76) and death (HR: 1.99; 95% CI: 1.46-2.70) were greater in the low-dose group than in the standard-dose group in the UT analysis. Similar results were observed for the ITT analysis.. No significant differences were observed in the effectiveness or safety outcome between low-dose and standard-dose rivaroxaban, except for AMI. However, low-dose apixaban was associated with a greater risk of stroke/SE and death without a reduction in the bleeding rates.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Humans; Myocardial Infarction; Pyridones; Rivaroxaban; Stroke

Topics: Humans; Propensity Score; Rivaroxaban

There were limited data on the risk of post-polypectomy bleeding (PPB) in patients on direct oral anticoagulants (DOAC). We aimed to evaluate the PPB and thromboembolic risks among DOAC and warfarin users in a population-based cohort.. We performed a territory-wide retrospective cohort study involving patients in Hong Kong from 2012 to 2020. Patients who received an oral anticoagulant and had undergone colonoscopy with polypectomy were identified. Propensity-score models with inverse probability of treatment weighting were developed for the warfarin-DOAC and between-DOAC comparisons. The primary outcome was clinically significant delayed PPB, defined as repeat colonoscopy requiring haemostasis within 30 days. The secondary outcomes were 30-day blood transfusion requirement and new thromboembolic event.. Apixaban was associated with lower PPB risk than warfarin (adjusted HR (aHR) 0.39, 95% CI 0.24 to 0.63, p<0.001). Dabigatran (aHR 2.23, 95% CI 1.04 to 4.77, adjusted p (ap)=0.035) and rivaroxaban (aHR 2.72, 95% CI 1.35 to 5.48, ap=0.002) were associated with higher PPB risk than apixaban. In subgroup analysis, apixaban was associated with lower PPB risk in patients aged ≥70 years and patients with right-sided colonic polyps.For thromboembolic events, apixaban was associated with lower risk than warfarin (aHR 0.22, 95% CI 0.11 to 0.45, p<0.001). Dabigatran (aHR 2.60, 95% CI 1.06 to 6.41, ap=0.033) and rivaroxaban (aHR 2.96, 95% CI 1.19 to 7.37, ap =0.013) were associated with higher thromboembolic risk than apixaban.. Apixaban was associated with a significantly lower risk of PPB and thromboembolism than warfarin, dabigatran and rivaroxaban, particularly in older patients with right-sided polyps.

Topics: Aged; Anticoagulants; Blood Transfusion; Cohort Studies; Colonic Polyps; Colonoscopy; Dabigatran; Factor Xa Inhibitors; Gastrointestinal Hemorrhage; Hong Kong; Humans; Male; Postoperative Complications; Pyrazoles; Pyridones; Retrospective Studies; Risk Assessment; Rivaroxaban; Thromboembolism; Warfarin

Although not routinely recommended, anti-Xa level monitoring for apixaban or rivaroxaban may be useful in certain clinical scenarios. There are currently no laboratory standards, therapeutic ranges, or proven correlation between anti-Xa levels and clinical outcomes.. This study describes the utilization, application, and association of anti-Xa levels with clinical outcomes in patients receiving apixaban or rivaroxaban.. This retrospective, descriptive study included adult inpatients within the Houston Methodist System on apixaban or rivaroxaban with at least one anti-Xa level ordered subsequent to administered doses. The primary endpoint was major bleeding according to International Society on Thrombosis and Haemostasis criteria. Secondary endpoints included reasons for anti-Xa level ordering, anti-Xa levels at different time intervals post-dose, and thrombotic events. Pre-specified subgroup analyses were performed to further evaluate the primary endpoint.. The study population consisted of 169 patients and 234 anti-Xa levels. Twenty-nine levels were obtained in context of major bleeding. The majority of levels were not drawn as peak levels 2-4 hours post-dose, however remained quantifiable above typical observed levels within this timeframe and well beyond 24 hours post-dose. Patient characteristics with major bleeding included elderly age, acute renal impairment, and low body weight. At least 14 unique reasons for anti-Xa level ordering were identified. Twenty-nine levels were associated with thrombotic events.. Anti-Xa levels may be useful for assessment of current drug concentrations, immediate safety of therapy, and guidance for possible clinical interventions. Dose titration and reversal therapies based on anti-Xa level results in major bleeding warrant further research.

Topics: Adult; Aged; Factor Xa Inhibitors; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Pyridones; Retrospective Studies; Rivaroxaban; Thrombosis

Limited data exists regarding the clinical outcomes of andexanet alfa and four factor prothrombin complex concentrate (4F-PCC) for reversal of apixaban or rivaroxaban in the setting of intracranial hemorrhage (ICH). The objective of this study was to evaluate clinical outcomes of 4F-PCC and andexanet alfa for reversal of ICH associated with oral factor Xa inhibitors. This was a retrospective, single-center, case series evaluating hemostatic efficacy of patients receiving andexanet alfa) or 4F-PCC for reversal of apixaban or rivaroxaban after ICH. Secondary endpoints included in-hospital mortality, thrombotic complications, timing of reversal agents, intensive care unit and hospital length of stay, patient disposition, and 30-day readmission rate. During the study period, 21 patients received andexanet alfa and 35 received 4F-PCC. Hemostatic efficacy occurred in 64.7% of patients receiving andexanet alfa and 54.8% of receiving 4F-PCC. Thirty-day all-cause mortality was 45.2% for 4F-PCC and 30% for andexanet alfa. Thrombotic events were higher with 4F-PCC (31.4%) compared to andexanet alfa (14.3%). Median time from presentation to administration of reversal agent was 2.67 [1.75-4.13] hours with andexanet alfa and 1.73 [1.21-3.55] hours with 4F-PCC. Discharge to skilled nursing facilities and 30-day readmission were similar between groups. In this cohort, reversal with andexanet alfa and 4F-PCC differed in terms ofhemostatic efficacy and thrombotic events after ICH in patients anticoagulated with apixaban or rivaroxaban.

Topics: Blood Coagulation Factors; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Intracranial Hemorrhages; Pyrazoles; Pyridones; Recombinant Proteins; Retrospective Studies; Rivaroxaban

Andexanet alfa, a modified recombinant factor Xa (FXa), was FDA approved in 2018 for anticoagulant reversal in patients with life-threatening bleeding associated with FXa inhibitors (FXaI). The ANNEXA-4 investigators administered andexanet alfa to patients within an 18-h from last dose of oral FXaI. In practice, time from last dose is often unknown. Previous studies have shown that clearance of these agents may be impaired by renal and hepatic dysfunction, as well as drug-drug interactions. Decision for use of andexanet alfa is also complicated by its high cost, limited drug availability, and thrombotic risk. This study aimed to describe the utility of anti-Xa DOAC levels as a decision point to administer andexanet alfa.. This is a case series of four patients with an anti-Xa DOAC level that received andexanet alfa for oral FXaI reversal in the setting of life-threatening bleeding or prior to procedure.. Four patients were included in the study. Two patients had a known time since last dose of oral FXaI. All patients had a detectable anti-Xa DOAC levels prior to administration of andexanet alfa. Two patients had levels within the peak range, one patient had a level below the peak range, and one patient had a level above the peak range. Andexanet alfa was administered after anti-Xa DOAC level return in all patients.. In our case series, obtaining anti-Xa DOAC levels prior to administration of andexanet alfa was achievable and facilitated use of reversal agents in patients with major bleeding or emergent procedural need.

Topics: Anticoagulants; Factor Xa; Factor Xa Inhibitors; Humans; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban

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

Limited data exist regarding the safety of ultrasound-guided femoral nerve blockade (US-FNB) in patients with hip fractures treated with anti-Xa direct oral anticoagulants (DOAC).. To compare the safety outcomes of US-FNB to conventional analgesia in patients with hip fractures treated with anti-Xa DOAC.. This observational exploratory prospective study included 69 patients who presented to our emergency department (ED) in 3 years with hip fracture and who were treated with apixaban or rivaroxaban. Patients received either a US-FNB (n=19) or conventional analgesics (n=50) based on their preference and, and the presence of a trained ED physician qualified in performing US-FNB. Patients were observed for major bleeding events during and 30 days after hospitalization. The degree of preoperative pain and opioid use were also observed.. We found no significant difference in the number of major bleeding events between groups (47.4% vs. 54.0%, P = 0.84). Degree of pain measured 3 and 12 hours after presentation was found to be lower in the US-FNB group (median visual analog scale of pain improvement from baseline of -5 vs. -3 (P = 0.002) and -5 vs.-4 (P = 0.023), respectively. Opioid administration pre-surgery was found to be more than three times more common in the conventional analgesia group (26.3% vs.80%, P < 0.0001).. Regarding patients treated with Anti-Xa DOAC, US-FNB was not associated with an increase in major bleeding events compared to conventional analgesia, although it was an effective means of pain alleviation. Larger scale randomized controlled trials are required to determine long-term safety and efficacy.

Topics: Aged; Aged, 80 and over; Analgesics; Analgesics, Opioid; Cohort Studies; Emergency Service, Hospital; Factor Xa Inhibitors; Female; Femoral Nerve; Hemorrhage; Hip Fractures; Humans; Male; Nerve Block; Pain Measurement; Pain, Postoperative; Pilot Projects; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban; Ultrasonography, Interventional

Major atrial fibrillation (AF) guidelines recommend non-vitamin K antagonist oral anticoagulants (NOACs) over warfarin, except in rare clinical circumstances based on 4 randomized controlled trials comparing each NOAC with warfarin. We aimed to investigate the current NOAC prescription behaviors in alignment with the recent clinical evidence available.. We conducted a cross-sectional analysis of NOAC-using patients with non-valvular atrial fibrillation (NVAF) who were aged ≥65 years on the index date (July 1, 2018) based on nationwide claims data. The types of NOACs being taken were analyzed using chi-squared tests, and factors influencing NOAC selection were identified using multinomial logistic regression analysis.. A total of 6,061 patients were included. Among the 4 NOACs, rivaroxaban was the most used NOAC. Patients aged ≥75 years (odds ratio [OR] = 1.270, confidence interval [CI] = 1.089-1.450) and women (OR = 1.148, CI = 1.011-1.284) were more likely to use apixaban relative to rivaroxaban. Patients with prior stroke/transient ischemic attack/thromboembolism had higher odds of using dabigatran (OR = 1.508, CI = 1.312-1.704) and apixaban (OR = 1.186, CI = 1.026-1.346). Patients with renal disease had higher odds of using apixaban (OR = 1.466, 95% CI = 1.238-1.693). These findings are consistent with the efficacy and safety profiles reported in pivotal trials and observational studies comparing individual NOACs.. Among the 4 NOACs, rivaroxaban was the most commonly used NOAC. Apixaban was preferred for patients aged ≥75 years, females, and patients with renal disease.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cross-Sectional Studies; Factor Xa Inhibitors; Female; Humans; Male; Practice Patterns, Physicians'; Pyrazoles; Pyridones; Republic of Korea; Rivaroxaban; Stroke

Gastrointestinal bleeding (GIB) rates for direct oral anticoagulants (DOACs) and warfarin have been extensively compared. However, population-based studies comparing GIB rates among different DOACs are limited.. To compare rates of GIB among apixaban, dabigatran, and rivaroxaban.. Nationwide population-based cohort study.. Landspítali-The National University Hospital of Iceland and the 4 regional hospitals in Iceland.. New users of apixaban, dabigatran, and rivaroxaban from 2014 to 2019.. Rates of GIB were compared using inverse probability weighting, Kaplan-Meier survival estimates, and Cox regression.. In total, 2157 patients receiving apixaban, 494 patients receiving dabigatran, and 3217 patients receiving rivaroxaban were compared. For all patients, rivaroxaban had higher overall rates of GIB (3.2 vs. 2.5 events per 100 person-years; hazard ratio [HR], 1.42 [95% CI, 1.04 to 1.93]) and major GIB (1.9 vs. 1.4 events per 100 person-years; HR, 1.50 [CI, 1.00 to 2.24]) compared with apixaban. Rivaroxaban also had higher GIB rates than dabigatran, with similar point estimates, although the CIs were wider and included the possibility of a null effect. When only patients with atrial fibrillation were included, rivaroxaban was associated with higher rates of overall GIB than apixaban (HR, 1.40 [CI, 1.01 to 1.94]) or dabigatran (HR, 2.04 [CI, 1.17 to 3.55]). Dabigatran was associated with lower rates of upper GIB than rivaroxaban in both analyses.. Unmeasured confounding and small subgroup analyses.. Rivaroxaban was associated with higher GIB rates than apixaban and dabigatran regardless of treatment indication.. Icelandic Centre for Research and Landspítali-The National University Hospital of Iceland.

Topics: Aged; Cohort Studies; Dabigatran; Digestive System Diseases; Factor Xa Inhibitors; Female; Follow-Up Studies; Gastrointestinal Hemorrhage; Humans; Iceland; Male; Propensity Score; Pyrazoles; Pyridones; Rivaroxaban; Ulcer

It is unclear whether elderly patients established on direct oral anticoagulants (DOACs) have greater exposure to these drugs, which could subsequently increase their risk of bleeding. We assessed DOAC exposure and factors affecting it in a real-world elderly cohort of patients. For this, 151 medically stable hospital inpatients (76 established on apixaban, 61 on rivaroxaban, 14 on dabigatran) with a median [interquartile range (IQR)] age of 84 (78-89) years were recruited. Patients provided blood samples for measurement of peak and trough plasma DOAC concentrations. There was up to 48-fold and 13-fold variation in trough and peak plasma drug concentrations respectively. A significantly greater proportion of patients on apixaban had peak plasma drug concentrations within the reported ranges compared to those on either rivaroxaban or dabigatran (82·9% vs. 44·3% vs. 64·3% respectively; P < 0·001). A third of the variability in DOAC plasma concentrations was attributed to the influences of DOAC dosage, renal function and gender. To what extent the observed increases in DOAC exposure in the older patients is the cause of their increased risk of bleeding, which could potentially be ameliorated by dosing titration, requires further investigation.

Topics: Age Factors; Aged; Aged, 80 and over; Dabigatran; Drug Monitoring; Factor Xa Inhibitors; Female; Hospitalization; Humans; Male; Pyrazoles; Pyridones; Rivaroxaban; Thrombosis

Direct oral anticoagulants (DOAC) use remains challenging in obese patients treated for Venous-Thrombo-Embolism (VTE) due to the paucity of prospective and dedicated studies.. To assess rivaroxaban and apixaban concentrations at different time-points after intake, in obese patients followed at a thrombosis center and treated for VTE; to define factors associated with DOAC levels outside the on-therapy ranges; and to evaluate bleeding and thrombosis rates during follow-up.. Observational prospective study in two French University hospitals. Apixaban or rivaroxaban concentrations were measured after the first visit, regardless of last intake in obese patients receiving DOAC for VTE. Concentrations were compared to published reference values for non-obese patients. Demographic, clinical, biological and therapeutic data were collected. Univariate and multivariate analyses were performed to identify factors associated to DOAC concentrations outside the on-therapy ranges.. Out of the 146 patients included, 22 (15%) had DOAC concentrations outside the on-therapy ranges, mainly in the rivaroxaban group (n = 17). Age ≤ 63 years, use of rivaroxaban and time since last intake ≤8 h were associated with DOAC concentrations outside the on-therapy ranges, in multivariable analysis. During the median follow-up of 16 months, two (1%) patients receiving apixaban had recurrent VTE. No patient had major bleeding, 11 (8%) patients had minor bleeding.. In this specific prospective bi-centric study dedicated to VTE obese patients, use of DOACs at fixed doses led to concentrations similar to those of non-obese patients in a high proportion of patients, without any effect of the BMI, and with risk-benefit profile comparable to non-obese patients.

Topics: Humans; Middle Aged; Obesity; Pharmaceutical Preparations; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban; Venous Thromboembolism

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

Direct-acting oral anticoagulants (DOACs) vary in bioavailability and sites of absorption in the gastrointestinal tract (GIT). Data on DOAC use after major GIT surgery are limited. The aim of this case series was to report the impact of surgical resection or bypass of the GIT on rivaroxaban and apixaban peak plasma concentrations. This was a case series of patients who received rivaroxaban or apixaban after GIT surgery, during the period of July 1, 2019, to December 31, 2020. Peak plasma concentrations of rivaroxaban and apixaban were assessed for the expected concentrations. Of the 27 assessed patients, 18 (66.7%) received rivaroxaban, and 9 (33.3%) received apixaban. After rivaroxaban therapy, 4 of 5 patients (80%) who underwent gastrectomy, and 3 of 3 patients (100%) who underwent duodenum and proximal jejunum exclusion had peak plasma concentrations of rivaroxaban lower than the effective range, whereas 11 of 11 patients (100%) who underwent distal bowel or ileostomy had peak rivaroxaban plasma within the effective range. After apixaban therapy, 5 of 6 patients (83.3%) who underwent total or partial gastrectomy achieved effective peak concentrations. All the patients who underwent proximal and distal bowel resection or bypass had peak concentrations of apixaban within the effective range. In conclusion, surgical resection or bypass of the upper GIT could affect DOAC absorption and subsequently peak plasma concentrations. This effect was more observed among rivaroxaban recipients. An injectable anticoagulant or vitamin K antagonist may be preferred if DOAC concentrations cannot be measured after GIT surgery.

Topics: Administration, Oral; Adult; Aged; Biological Availability; Digestive System Surgical Procedures; Drug Monitoring; Factor Xa Inhibitors; Female; Gastric Absorption; Gastrointestinal Tract; Humans; Intestinal Absorption; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban

The purpose of this study is to investigate the correlation between glomerular filtration rate (GFR) estimated by different renal function equations and non-vitamin K antagonist oral anticoagulant concentration. Atrial fibrillation patients who aged ≥ 20 years and used dabigatran, rivaroxaban, or apixaban for thromboembolism prevention were enrolled to collect blood samples and measure drug concentrations using ultra-high-performance liquid chromatography with tandem mass spectrometry. The GFR was estimated using the Cockroft-Gault formula (abbreviated as creatinine clearance, CrCL), Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) featuring both creatinine and cystatin C, and the Modification of Diet in Renal Disease Study equation (MDRD). Multivariate regression was used to investigate the associations of different renal function estimates with drug concentrations. A total of 511 participants were enrolled, including 146 dabigatran users, 164 rivaroxaban users and 201 apixaban users. Compared to clinical trials, 35.4% of dabigatran, 4.9% of rivaroxaban, and 5.5% of apixaban concentrations were higher than the expected range (p < 0.001). CKD-EPI and MDRD estimates classified fewer patients as having GFR < 50 mL/min than CrCL in all 3 groups. Both CrCL and CKD-EPI were associated with higher-than-expected ranges of dabigatran or rivaroxaban concentrations. Nevertheless, none of the renal function equations was associated with higher-than-expected apixaban concentrations. For participants aged ≥ 75 years, CKD-EPI may be associated with higher-than-expected trough concentration of dabigatran. In conclusion, CrCL and CKD-EPI both can be used to identify patients with high trough concentrations of dabigatran or rivaroxaban. Among elderly patients who used dabigatran, CKD-EPI may be associated with increased drug concentration.

Topics: Adult; Aged; Aged, 80 and over; Antithrombins; Creatinine; Cystatin C; Dabigatran; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban; Vitamin K

The comparative effectiveness of rivaroxaban and apixaban, the most frequently prescribed oral anticoagulants for ischemic stroke prevention in patients with atrial fibrillation, is uncertain.. To compare major ischemic and hemorrhagic outcomes in patients with atrial fibrillation treated with rivaroxaban or apixaban.. Retrospective cohort study using computerized enrollment and claims files for US Medicare beneficiaries 65 years or older. Between January 1, 2013, and November 30, 2018, a total of 581 451 patients with atrial fibrillation began rivaroxaban or apixaban treatment and were followed up for 4 years, through November 30, 2018.. Rivaroxaban (n = 227 572) and apixaban (n = 353 879), either standard or reduced dose.. The primary outcome was a composite of major ischemic (stroke/systemic embolism) and hemorrhagic (intracerebral hemorrhage/other intracranial bleeding/fatal extracranial bleeding) events. Secondary outcomes were nonfatal extracranial bleeding and total mortality (fatal ischemic/hemorrhagic event or other death during follow-up). Rates, hazard ratios (HRs), and rate differences (RDs) were adjusted for baseline differences in comorbidity with inverse probability of treatment weighting.. Study patients (mean age, 77.0 years; 291 966 [50.2%] women; 134 393 [23.1%] receiving reduced dose) had 474 605 person-years of follow-up (median [IQR] of 174 [62-397] days). The adjusted primary outcome rate for rivaroxaban was 16.1 per 1000 person-years vs 13.4 per 1000 person-years for apixaban (RD, 2.7 [95% CI, 1.9-3.5]; HR, 1.18 [95% CI, 1.12-1.24]). The rivaroxaban group had increased risk for both major ischemic events (8.6 vs 7.6 per 1000 person-years; RD, 1.1 [95% CI, 0.5-1.7]; HR, 1.12 [95% CI, 1.04-1.20]) and hemorrhagic events (7.5 vs 5.9 per 1000 person-years; RD, 1.6 [95% CI, 1.1-2.1]; HR, 1.26 [95% CI, 1.16-1.36]), including fatal extracranial bleeding (1.4 vs 1.0 per 1000 person-years; RD, 0.4 [95% CI, 0.2-0.7]; HR, 1.41 [95% CI, 1.18-1.70]). Patients receiving rivaroxaban had increased risk of nonfatal extracranial bleeding (39.7 vs 18.5 per 1000 person-years; RD, 21.1 [95% CI, 20.0-22.3]; HR, 2.07 [95% CI, 1.99-2.15]), fatal ischemic/hemorrhagic events (4.5 vs 3.3 per 1000 person-years; RD, 1.2 [95% CI, 0.8-1.6]; HR, 1.34 [95% CI, 1.21-1.48]), and total mortality (44.2 vs 41.0 per 1000 person-years; RD, 3.1 [95% CI, 1.8-4.5]; HR, 1.06 [95% CI, 1.02-1.09]). The risk of the primary outcome was increased for rivaroxaban in both those receiving the reduced dose (27.4 vs 21.0 per 1000 person-years; RD, 6.4 [95% CI, 4.1-8.7]; HR, 1.28 [95% CI, 1.16-1.40]) and the standard dose (13.2 vs 11.4 per 1000 person-years; RD, 1.8 [95% CI, 1.0-2.6]; HR, 1.13 [95% CI, 1.06-1.21]) groups.. Among Medicare beneficiaries 65 years or older with atrial fibrillation, treatment with rivaroxaban compared with apixaban was associated with a significantly increased risk of major ischemic or hemorrhagic events.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Embolism; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Intracranial Hemorrhages; Male; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke

To assess the safety of needle electromyography in patients on non-vitamin K oral anticoagulants (NOACs) compared with warfarin.. A retrospective chart review was done in patients who underwent needle electromyography studies while they were using warfarin and NOACs. After the needle electromyography, all the patients were monitored for 2 hours and ultrasound of high-risk muscle groups was done. The complications were classified based on the International Society on Thrombosis and Hemostasis definitions.. Fifty-eight patients were included: 29 were using NOACs and the other 29 were on warfarin. The mean age was 59.33 ± 16 years. Hemorrhagic complications from needle electromyography were noted in 9 patients: 7 (77.7%) NOACs and 2 (22.3%) warfarin. Among them, 6 patients (66.6%) met the diagnostic criteria for Clinically Relevant Non-Major Bleeding criteria proposed by International Society on Thrombosis and Hemostasis and 3 patients (33.4%) had an asymptomatic hematoma on ultrasound evaluation. A total of 267 muscles were tested and only 9 (3.3%) muscles had hemorrhagic complications. One patient (rivaroxaban) had acute bleeding requiring pressure bandage, five patients (two apixaban, two rivaroxaban, and one warfarin) had clinical hematoma that required ice packs, and three patients (two rivaroxaban and one warfarin) had a hematoma on ultrasound of deep muscles.. Patients on NOACs had minimal risk of clinically relevant hemorrhagic complications, and the risk is not significantly different from those on warfarin.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Dabigatran; Electromyography; Female; Hematoma; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Warfarin

The prevalence of direct oral anticoagulants (DOACs) has increased with continued evidence of their efficacy and ease of use. However, the rise in their utilization also surfaced a concern regarding their reversal in patients actively bleeding and/or those requiring invasive procedures. Up until 2018, there were several reversal options available including 4-factor prothrombin complex concentrate (4-factor PCC), activated charcoal, desmopressin, and tranexamic acid. Then, in 2018, andexanet alpha, a recombinant factor Xa, was approved for the reversal of apixaban and rivaroxaban in patients with life-threatening or uncontrolled bleeding. Nonetheless, because 4-factor PCC is more easily attainable and cost-effective, it continues to be the more favorable option for many health-care professionals.. This retrospective chart review was conducted at NYU Winthrop Hospital in patients who received 4-factor PCC for the reversal of DOACs from January 2018 to July 2018. Patient charts were reviewed and relevant data was collected (admitting diagnosis, dose of 4-factor PCC utilized, etc).. Fifty-three patients were evaluated with 85% experiencing a positive response and complete recovery following the administration of 4-factor PCC; 8 (15%) patients died after receiving 4-factor PCC, none as a result of its administration; 3 patients died secondary to other underlying comorbidities, 4 patients died due to an intracranial hemorrhage, and 1 died due to hematoma of the tongue.. Based on the results thus far, the use of 4-factor PCC may be a good treatment option in patients requiring DOAC reversal.

Topics: Administration, Oral; Anticoagulants; Blood Coagulation Factors; Humans; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban

To analyze the efficacy and safety of activated prothrombin complex concentrates (aPCC) and four-factor prothrombin complex concentrates (4F-PCC) to prevent hematoma expansion in patients taking apixaban or rivaroxaban with intracranial hemorrhage (ICH). In this multicenter, retrospective study, sixty-seven ICH patients who received aPCC or 4F-PCC for known use of apixaban or rivaroxaban between February 2014 and September 2018 were included. The primary outcome was the percentage of patients who achieved excellent/good or poor hemostasis after administration of aPCC or 4F-PCC. Secondary outcomes included hospital mortality, thromboembolic events during admission, and transfusion requirements. Excellent/good hemostasis was achieved in 87% of aPCC patients, 89% of low-dose 4F-PCC [< 30 units per kilogram (kg)], and 89% of high-dose 4F-PCC (≥ 30 units per kg). There were no significant differences in excellent/good or poor hemostatic efficacy (p = 0.362). No differences were identified in transfusions 6 h prior (p = 0.087) or 12 h after (p = 0.178) the reversal agent. Mortality occurred in five patients, with no differences among the groups (p = 0.838). There were no inpatient thromboembolic events. Both aPCC and 4F-PCC appear safe and equally associated with hematoma stability in patients taking apixaban or rivaroxaban who present with ICH. Prospective studies are needed to identify a superior reversal agent when comparing andexanet alfa to hospital standard of care (4F-PCC or aPCC) and to further explore the optimal dosing strategy for patients with ICH associated with apixaban or rivaroxaban use.

Topics: Aged; Aged, 80 and over; Blood Coagulation Factors; Factor Xa Inhibitors; Female; Humans; Intracranial Hemorrhages; Male; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban; Treatment Outcome

Patient frailty amongst patients with nonvalvular atrial fibrillation (NVAF) is associated with adverse health outcomes and increased risk of mortality. Additional evidence is needed to evaluate effective and safe NVAF treatment in this patient population.. This subgroup analysis of the ARISTOPHANES study compared the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) amongst frail NVAF patients prescribed nonvitamin K antagonist oral anticoagulants (NOACs) or warfarin.. This comparative retrospective observational study of frail, older NVAF patients who initiated apixaban, dabigatran, rivaroxaban or warfarin from 01JAN2013-30SEP2015 was conducted using Medicare and 3 US commercial claims databases. To compare each drug, 6 propensity score-matched (PSM) cohorts were created. Patient cohorts were pooled from 4 databases after PSM. Cox models were used to estimate hazard ratios (HR) of S/SE and MB.. Amongst NVAF patients, 34% (N = 150 487) met frailty criteria. Apixaban and rivaroxaban were associated with a lower risk of S/SE vs warfarin (apixaban: HR: 0.61, 95% CI: 0.55-0.69; rivaroxaban: HR: 0.79, 95% CI: 0.72-0.87). For MB, apixaban (HR: 0.62, 95% CI: 0.57-0.66) and dabigatran (HR: 0.79, 95% CI: 0.70-0.89) were associated with a lower risk and rivaroxaban (HR: 1.14, 95% CI: 1.08-1.21) was associated with a higher risk vs warfarin.. Amongst this cohort of frail NVAF patients, NOACs were associated with varying rates of stroke/SE and MB compared with warfarin. Due to the lack of real-world data regarding OAC treatment in frail patients, these results may inform clinical practice in the treatment of this patient population.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Cause of Death; Dabigatran; Frail Elderly; Hemorrhage; Humans; Propensity Score; Pyrazoles; Pyridones; Retrospective Studies; Risk Factors; Rivaroxaban; Stroke; United States; Vitamin K; Warfarin

Delayed bleeding after gastric endoscopic submucosal dissection (ESD) in patients receiving anticoagulants remains an unpreventable adverse event. Although direct-acting oral anticoagulants (DOACs) have superior efficacy in preventing thromboembolism, their effects on the occurrence of delayed bleeding remain unclear. This study aimed to elucidate the clinical effect of DOACs on delayed bleeding after gastric ESD.. We retrospectively examined 728 patients who received anticoagulants and were treated for gastric neoplasms with ESD in 25 institutions across Japan. Overall, 261 patients received DOACs, including dabigatran (92), rivaroxaban (103), apixaban (45) and edoxaban (21), whereas 467 patients were treated with warfarin.. Delayed bleeding occurred in 14% of patients taking DOACs, which was not considerably different in patients receiving warfarin (18%). Delayed bleeding rate was significantly lower in patients receiving dabigatran than in those receiving warfarin and lower than that observed for other DOACs. Multivariate analysis showed that age ≥ 65, receiving multiple antithrombotic agents, resection of multiple lesions and lesion size ≥ 30 mm were independent risk factors, and that discontinuation of anticoagulants was associated with a decreased risk of bleeding. In multivariate analysis among patients taking DOACs, dabigatran therapy was associated with a significantly lower risk of delayed bleeding.. The effects of DOACs on delayed bleeding varied between agents, but dabigatran therapy was associated with the lowest risk of delayed bleeding. Switching oral anticoagulants to dabigatran during the perioperative period could be a reasonable option to reduce the risk of delayed bleeding after gastric ESD.

Topics: Aged; Aged, 80 and over; Anticoagulants; Dabigatran; Endoscopic Mucosal Resection; Female; Humans; Japan; Male; Middle Aged; Postoperative Complications; Postoperative Hemorrhage; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Rivaroxaban; Stomach; Stomach Neoplasms; Thiazoles; Thromboembolism; Warfarin

Topics: Administration, Oral; Aged; Anticoagulants; Clopidogrel; Drug Interactions; Drug Therapy, Combination; Female; Germany; Humans; Male; Percutaneous Coronary Intervention; Platelet Function Tests; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban

Despite their usefulness in perioperative and acute care settings, factor-Xa inhibitor-specific assays are scarcely available, contrary to heparin anti-Xa assay. We assessed whether the heparin anti-Xa assay can (1) be used as a screening test to rule out apixaban, rivaroxaban, fondaparinux, and danaparoid levels that contraindicate invasive procedures according to current guidelines (>30 ng·mL-1, >30 ng·mL-1, >0.1 µg·mL-1, and >0.1 IU·mL-1, respectively), (2) quantify the anticoagulant level if found significant, that is, if it exceeded the abovementioned threshold.. In the derivation cohort then in the validation cohort, via receiver operating characteristics (ROC) curve analysis, we evaluated the ability of heparin anti-Xa assay to detect levels of factor-Xa inhibitors above or below the abovementioned safety thresholds recommended for an invasive procedure (screening test). Among samples with relevant levels of factor-Xa inhibitor, we determined the conversion factor linking the measured level and heparin anti-Xa activity in a derivation cohort. In a validation cohort, the estimated level of each factor-Xa inhibitor was thus inferred from heparin anti-Xa activity. The agreement between measured and estimated levels of factor-Xa inhibitors was assessed.. Among 989 (355 patients) and 756 blood samples (420 patients) in the derivation and validation cohort, there was a strong linear relationship between heparin anti-Xa activities and factor-Xa inhibitors measured level (r = 0.99 [95% confidence interval {CI}, 0.99-0.99]). In the derivation cohort, heparin anti-Xa activity ≤0.2, ≤0.3, <0.1, <0.1 IU·mL-1 reliably ruled out a relevant level of apixaban, rivaroxaban, fondaparinux, and danaparoid, respectively (area under the ROC curve ≥0.99). In the validation cohort, these cutoffs yielded excellent classification accuracy (≥96%). If this screening test indicated relevant level of factor-Xa inhibitor, estimated and measured levels closely agreed (Lin's correlation coefficient close to its maximal value: 95% CI, 0.99-0.99). More than 96% of the estimated levels fell into the predefined range of acceptability (ie, 80%-120% of the measured level).. A unique simple test already widely used to assay heparin was also useful for quantifying these 4 other anticoagulants. Both clinical and economic impacts of these findings should be assessed in a specific study.

Topics: Blood Coagulation; Blood Coagulation Tests; Chondroitin Sulfates; Dermatan Sulfate; Drug Monitoring; Factor Xa Inhibitors; Fondaparinux; France; Heparitin Sulfate; Humans; Predictive Value of Tests; Pyrazoles; Pyridones; Reproducibility of Results; Retrospective Studies; Rivaroxaban

The authors report a case of intraoperative reversal of apixaban with andexanet alfa in a patient supported with venoarterial extracorporeal membrane oxygenation due to low- cardiac-output immediately after surgery for acute type A aortic dissection and massive intraoperative transfusion with administration of procoagulants. In this patient, andexanet alfa's off-label use was not associated with acute thrombotic complications despite being given during extracorporeal life support and after previous administration of prothrombin complex concentrates.

Topics: Aortic Dissection; Extracorporeal Membrane Oxygenation; Factor Xa; Factor Xa Inhibitors; Humans; Off-Label Use; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban

 There are acute settings where assessing the anticoagulant effect of direct oral anticoagulants (DOACs) can be useful. Due to variability among routine coagulation tests, there is an unmet need for an assay that detects DOAC effects within minutes in the laboratory or at the point of care..  We developed a novel dielectric microsensor, termed ClotChip, and previously showed that the time to reach peak permittivity (.  We accrued 154 individuals: 50 healthy volunteers, 49 rivaroxaban patients, 47 apixaban, and 8 dabigatran patients. Blood samples underwent ClotChip measurements and plasma coagulation tests. Control mean.  This diagnostic study using samples from "real-world" DOAC patients supports that ClotChip exhibits high sensitivity at detecting DOAC anticoagulant effects in a disposable portable platform, using a miniscule amount of whole blood (<10 µL).

Topics: Aged; Aged, 80 and over; Blood Coagulation; Blood Coagulation Tests; Dabigatran; Drug Monitoring; Equipment Design; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban

The management of patients with atrial fibrillation (AF) has rapidly changed with increasing use of non-vitamin K antagonist oral anticoagulants (NOACs) and changes in the use of rhythm control therapy. The prevention of thromboembolic events European Registry in Atrial Fibrillation Prolongation Registry (PREFER Prolongation) enrolled consecutive patients with AF on NOACs between 2014 and 2016 in a multicentre, prospective, observational study with one-year follow-up, focusing on the time of introduction of NOACs. Overall, 3783 patients were enrolled, with follow-up information available in 3223 (85%). Mean age was 72.2 ± 9.4 years, 40% were women, mean CHA

Topics: Administration, Oral; Aged; Atrial Fibrillation; Dabigatran; Europe; Factor Xa Inhibitors; Female; Humans; Male; Prospective Studies; Pyrazoles; Pyridones; Registries; Rivaroxaban

Despite a tremendous increase of direct oral anticoagulants (DOACs) prescriptions in recent years, only few data is available analysing prescribers' adherence to Summary of Product Characteristics (SmPC). We aimed to assess adherence to registered indications, contraindications, special warnings/precautions, and potential drug-drug interactions for three DOAC compounds (dabigatran, rivaroxaban, and apixaban) in six databases of five European countries (The Netherlands, United Kingdom, Spain, Denmark, and Germany). We included adult patients (≥18 years) initiating DOACs between 2008 and 2015. For several SmPC items, broad definitions were used due to ambiguous SmPC terms or lacking data in some databases. Within the study period, a DOAC was initiated in 407 576 patients (rivaroxaban: 240 985 (59.1%), dabigatran: 95 303 (23.4%), and apixaban: 71 288 (17.5%)). In 2015, non-valvular atrial fibrillation was the most common indication (>60% in most databases). For the whole study period, a substantial variation between the databases was found regarding the proportion of patients with at least one contraindication (inter-database range [IDR]: 8.2%-55.7%), with at least one special warning/precaution (IDR: 35.8%-75.2%) and with at least one potential drug-drug interaction (IDR: 22.4%-54.1%). In 2015, the most frequent contraindication was "malignant neoplasm" (IDR: 0.7%-21.3%) whereas the most frequent special warning/precaution was "prescribing to the elderly" (≥75 years; IDR: 25.0%-66.4%). The most common single compound class interaction was "concomitant use of non-steroidal anti-inflammatory drugs" (IDR: 3.0%-25.3%). Contraindications, special warnings/precautions, and potential drug-drug interactions were present in a relevant number of new DOAC users. Due to broad definitions used for some SmPC terms, overall proportions for contraindications are prone to overestimation. However, for unambiguous SmPC terms documented in the databases sufficiently, the respective estimates can be considered valid. Differences between databases might be related to "true" differences in prescription behaviour, but could also be partially due to differences in database characteristics.

Topics: Anticoagulants; Contraindications, Drug; Dabigatran; Drug Interactions; Drug Prescriptions; Drug Utilization; Humans; Pyrazoles; Pyridones; Rivaroxaban

Direct oral anticoagulants (DOACs), such as apixaban, rivaroxaban, and dabigatran, are increasingly being used to provide prophylaxis and treatment for arterial and venous thromboembolism. Multiple procedural subspecialties have implemented guidelines detailing time frames for perioperative DOAC interruption; however, the impact of perioperative DOAC interruption in patients undergoing dermatologic surgery is currently unknown, and evidence-based guidelines are lacking.. To assess the 30-day postoperative rate of thrombotic complications (ischemic stroke, transient ischemic attack, systemic embolism, deep vein thrombosis [DVT] and pulmonary embolism) in patients with nonvalvular atrial fibrillation (AF) or a history of DVT who underwent perioperative DOAC interruption during dermatologic surgery.. A retrospective medical record review was performed of all patients with AF or a history of DVT who underwent perioperative DOAC interruption during dermatologic surgery at Advanced Dermatologic Surgery and the University of Kansas Medical Center between January 1, 2016, and August 31, 2020.. Among 806 operations, comprising 750 Mohs micrographic operations (93.1%) and 56 excisions (6.9%), 1 patient (0.14% of patients with AF) sustained a transient ischemic attack and 2 patients (0.25% of all patients) sustained minor bleeding complications during the 30-day postoperative period.. Perioperative DOAC interruption appears to be safe and efficacious in dermatologic surgery.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Dermatologic Surgical Procedures; Female; Humans; Ischemic Attack, Transient; Male; Perioperative Care; Postoperative Hemorrhage; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban

Direct factor Xa inhibitors, such as apixaban and rivaroxaban, are widely used for treatment and prevention of venous thromboembolism; however, recent cases of therapeutic failure have been reported. Potential risk factors associated with therapeutic failure such as dose deviations outside of package labeling recommendations, and the use of direct factor Xa-specific inhibitor levels to guide clinical decision making continue to be areas of further investigation. Our study aimed to describe characteristics and dosing regimens in patients on apixaban or rivaroxaban who experienced a new or recurrent thrombosis. We performed a retrospective chart review on 190 patients on either apixaban or rivaroxaban presenting to our institution with new or breakthrough thromboembolism. Evaluation of prescribed anticoagulation regimens compared to package labeling recommendations, direct factor Xa inhibitor-specific anti-Xa levels, anticoagulation interruptions, use of parenteral bridge anticoagulation, final anticoagulation regimen disposition, and thrombosis-associated mortality were recorded. In patients presenting with breakthrough thromboembolism, 78% were on a regimen that matched package labeling recommendations. Anti-Xa levels were documented in 66 patients, the majority of which fell within institutional expected ranges at time of thrombosis. Therapy interruptions immediately prior to thrombosis were observed in 22% of patients and 21% of those patients received parenteral anticoagulation during interruption. Upon discharge, 46% of patients continued the same anticoagulation regimen with no changes. The mortality rate was 6%. In patients who present with new thromboembolism on apixaban or rivaroxaban, a thorough review of risks and benefits should be conducted to mitigate future risk of recurrent thrombosis.

Topics: Anticoagulants; Factor Xa Inhibitors; Humans; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; 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

It is unclear if stopping treatment with dabigatran, a new oral anticoagulant (NOAC), induces a paradoxical rebound prothrombotic state. We investigated if short-term (1-3 days) dabigatran cessation is associated with a higher thrombus volume than expected from a simple reversal of the anticoagulant effect.. Ten-week-old C57Bl/6 mice (n = 338) received one of the following oral treatments: phosphate-buffered saline (PBS), dabigatran for 7 days with or without 1 to 4 day cessation, and aspirin in either a single dose or daily for 7 days. Some of the animals that ceased dabigatran for 1 to 3 days received single-dose aspirin. Thereafter, we induced FeCl. We observed a ~ 40% higher volume of carotid thrombus after dabigatran cessation at 1 to 3 days than after vehicle treatment and showed that this effect could be prevented by single-dose aspirin pretreatment. Dabigatran cessation unduly increased platelet aggregability for 2 days after drug cessation, an effect mediated through thrombin or arachidonic acid, which effect was significantly attenuated by single-dose aspirin pretreatment. In patients, short-term (≤ 3 days) cessation of NOAC therapy, compared with longer-term (≥ 5 days) cessation, tended to be associated with relatively high stroke severity.. We provide the first preclinical evidence that a rebound prothrombotic state follows short-term cessation of dabigatran therapy. ANN NEUROL 2021;89:444-458.

Topics: Aged; Aged, 80 and over; Animals; Antithrombins; Arachidonic Acid; Aspirin; Carotid Artery Thrombosis; Cerebral Infarction; Chlorides; Computed Tomography Angiography; Dabigatran; Deprescriptions; Factor Xa Inhibitors; Female; Ferric Compounds; Humans; Ischemic Stroke; Magnetic Resonance Angiography; Male; Mean Platelet Volume; Mice; Noxae; Pilot Projects; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Count; Pyrazoles; Pyridones; Rivaroxaban; Severity of Illness Index; Substance Withdrawal Syndrome; Thrombin; Thrombophilia; X-Ray Microtomography

We investigated factors that influenced oral anticoagulant (OAC) initiation and choice in Australian general practice patients newly diagnosed with AF.. Using an Australian nationally representative general practice dataset, MedicineInsight, we identified patients newly diagnosed with AF between January 2009 and April 2019. Logistic regression analyses were used to examine factors associated with OAC initiation and choice.. A total of 63 212 patients with AF (53.7% males, mean age 72.4 years) were identified. Nearly two-thirds of these patients (40 854 [64.6%]) were initiated on an OAC, at a median time of 6 days after the documented diagnosis date. The proportion of patients who were initiated an OAC increased from 44.8% in 2009 to 72.2% in 2019 (P < .001). High risk of stroke (CHA. The proportion of newly diagnosed patients with AF initiated on OAC increased markedly following the introduction of the DOACs. Of those initiated, 9 in 10 were receiving a DOAC at the end of the study period. There is potential underuse in women and individuals with dementia.

Topics: Age Factors; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Australia; Dabigatran; Factor Xa Inhibitors; Female; General Practice; Geography; Humans; Logistic Models; Male; Middle Aged; Practice Patterns, Physicians'; Pyrazoles; Pyridones; Rivaroxaban; Sex Factors; Stroke; Warfarin

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

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

Direct oral anticoagulants (DOAC) are hydrophilic drugs with plasma levels inversely proportional to lean body mass. Sarcopenic patients with low muscle mass may be at risk for supra-therapeutic DOAC levels and bleeding complications. We therefore sought to examine the influence of lean body mass on DOAC levels in older adults with atrial fibrillation (AF).. A prospective cohort study was conducted with patients 65 years of age or more receiving rivaroxaban or apixaban for AF. Appendicular lean mass (ALM) was measured using a bioimpedance device and a dual X-ray absorptiometry scanner. DOAC levels were measured using a standardized anti-Xa assay 4 hours after (peak) and 1 hour before (trough) ingestion.. The cohort consisted of 62 patients (47% female, 77.0 ± 6.1 years). The prescribed DOACs were apixaban 2.5 mg (21%), apixaban 5 mg (53%), and rivaroxaban 20 mg (26%). Overall, 16% had supra-therapeutic DOAC levels at trough and 25% at peak. In the multivariable logistic regression model, lower ALM was independently associated with supra-therapeutic DOAC levels at trough (odds ratio per ↓ 1-kg 1.23, 95% confidence interval 1.02 to 1.49) and peak (odds ratio per ↓ 1-kg 1.18, 95% confidence interval 1.02 to 1.37). Addition of ALM to a model consisting of age, total body weight, and renal function resulted in improved discrimination for supra-therapeutic DOAC levels.. Our proof-of-concept study has identified an association between ALM and DOAC levels in older adults with AF. Further research is needed to determine the impact of ALM on bleeding complications and the potential role of ALM-guided dosing for sarcopenic patients.

Topics: Absorptiometry, Photon; Aged; Atrial Fibrillation; Blood Coagulation Tests; Body Mass Index; Drug Dosage Calculations; Drug Monitoring; Electric Impedance; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Kidney Function Tests; Male; Proof of Concept Study; Pyrazoles; Pyridones; Rivaroxaban; Sarcopenia; Stroke; Thinness

Observational studies assessing direct oral anticoagulant (DOACs) dosage in atrial fibrillation (AF) reported that a lower proportion of patients received high-dose DOACs compared to those in randomized controlled trials (RCTs). Effectiveness and safety of high-dose DOACs relative to apixaban in a real-world AF population need to be addressed. The aim is to assess comparative effectiveness and safety of high-dose rivaroxaban relative to apixaban.. We conducted a cohort study. Setting We built a cohort of patients hospitalized and discharged in community with a primary or secondary AF diagnosis from 2011-2017 using Quebec administrative databases (Med-Echo and RAMQ). Patients Cohort entry was defined as the first OAC claim in new users of high-dose rivaroxaban and apixaban, with no OAC claims in the prior year. Intervention To compare effectiveness and safety of high-dose rivaroxaban to apixaban. Measurement We ascertained patient demographics, comorbidities, CHA2DS2-VASc and HASBLED scores and Charlson score within 3 years prior to cohort entry. Primary effectiveness and safety were a composite of ischemic stroke/systemic thrombosis, death, myocardial infarction, and of intracranial bleeding (ICH), extracranial major bleeding, in the first year following drug initiation. We conducted propensity score matching and estimated hazard ratios (HRs) for outcomes using Cox proportional hazard models. All the analyses were conducted to account for competing risks. Main results The cohort consisted of 4,632 and 6,771 patients received high-dose rivaroxaban and apixaban, respectively. High-dose rivaroxaban users were younger with a mean age of 73.2 years, presented less associated comorbidities and had lower CHA2DS2-VASc scores compared to apixaban. High-dose rivaroxaban at the intention to treat was associated with a higher risk of stroke/SE/death (HR 1.21, 95% CI 1.04-1.40) and worse composite effectiveness (HR 1.21: 1.05-1.40); under treatment exposure, those values were at HR (1.66: 1.21-2.29) and HR (1.58:1.19-2.10), respectively. And, rivaroxaban presented a less favorable safety profile relative to apixaban. Conclusion In this study, composite effectiveness and safety varied between rivaroxaban and apixaban. High-dose apixaban was observed to have a better effectiveness and safety.

Topics: Aged; Atrial Fibrillation; Cohort Studies; Dose-Response Relationship, Drug; Humans; Propensity Score; Pyrazoles; Pyridones; Rivaroxaban; Treatment Outcome

Idarucizumab reverses the anticoagulant dabigatran; it is recommended during intravenous thrombolysis treatment of dabigatran-treated patients with acute ischemic stroke (AIS) and in dabigatran-treated patients with intracranial hemorrhage (ICH).. Outcomes of consecutive idarucizumab/dabigatran-treated patients with intravenous thrombolysis-treated AIS (n = 22) were compared with consecutive similar intravenous thrombolysis-treated patients with AIS who were not anticoagulated (n = 182) [primary aim]; idarucizumab/dabigatran-treated patients with ICH (n = 13) were compared with patients with ICH who received the anticoagulants rivaroxaban or apixaban (n = 24) [secondary aim]. Efficacy was estimated by National Institutes of Health Stroke Scale score changes between admission and discharge and by the modified Rankin score after 3 months; safety was assessed by symptomatic ICH and mortality.. Basal neurological impairment was similar in both idarucizumab/dabigatran-treated and control groups of patients with AIS and ICH. The idarucizumab/dabigatran-treated patients with AIS with subsequent intravenous thrombolysis showed a mean National Institutes of Health Stroke Scale improvement of 84% vs 68% in the control group (p < 0.05). A favorable outcome (modified Rankin score ≤ 2 after 3 months) was achieved significantly more frequently than in the control group (86% vs 57%; p < 0.05). The complication rate was similar in both groups. In patients with ICH, a positive functional outcome (modified Rankin score ≤ 3 after 3 months) was achieved more often in the idarucizumab/dabigatran-treated group than in the control group (70% vs 42%; p = 0.109). The complication rate was similar.. Idarucizumab use in dabigatran-treated patients with AIS resulted in significantly more efficacious intravenous thrombolysis treatment and a non-significantly better outcome in dabigatran-treated patients with ICH compared with controls. There was no difference regarding complications.

Topics: Administration, Intravenous; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antithrombins; Dabigatran; Factor Xa Inhibitors; Female; Humans; Intracranial Hemorrhages; Ischemic Stroke; Male; Middle Aged; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban; Treatment Outcome

Thromboembolic events remain clinically unresolved after transcatheter aortic valve implantation (TAVI). The use of direct oral anticoagulant (DOAC) to reduce thrombosis associated with TAVI remains controversial. This study aimed at investigating the periprocedural change in blood coagulation and thrombolysis parameters in 199 patients undergoing transfemoral TAVI. Prothrombin activation fragment 1 + 2 (F1 + 2), thrombin-antithrombin complex (TAT), soluble fibrin monomer complex (SFMC), and fibrin/fibrinogen degradation product (FDP) levels were measured before and 1 hour after TAVI and 1, 2, and 7 days postoperatively. Of the 199 patients, 49 were treated with DOAC (apixaban in 32, edoxaban in 10, and rivaroxaban in 7). The F1 + 2 and TAT levels immediately increased 1 hour after TAVI and then gradually decreased in both groups. The SFMC level also significantly increased with a peak on day 1. The FDP level gradually increased, peaking on day 2. The values of F1 + 2, TAT, SFMC, and FDP in patients who used DOAC were significantly lower than those who did not use DOAC at 1 hour after TAVI in F1 + 2 (600 [452 to 765] vs 1055 [812 to 1340] pmol/L; p < 0.001), TAT (21.4 [16.2 to 37.0] vs 38.7 [26.4 to 58.7] μg/mL; p < 0.001) and on day 1 in SFMC (18.2 [9.4 to 57.9] vs 113.4 [70.9 to 157.3] μg/mL; p < 0.001) and day 2 in FDP (6.0 [4.7 to 10.0] vs 12.6 [8.2 to 17.4] μg/mL; p < 0.001). Ischemic stroke within 30 days after TAVI occurred in 3 patients (1.5%), who were not treated with DOAC. Coagulation cascade activation was observed after TAVI. DOAC could reduce transient hypercoagulation following TAVI.

Topics: Aged, 80 and over; Antithrombin III; Aortic Valve Stenosis; Blood Coagulation; Cohort Studies; Factor Xa Inhibitors; Female; Fibrin Fibrinogen Degradation Products; Humans; Male; Peptide Fragments; Peptide Hydrolases; Prothrombin; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thrombosis; Transcatheter Aortic Valve Replacement

Real-world predictors of major bleeding (MB) have been well-studied among warfarin users, but not among all direct oral anticoagulant (DOAC) users diagnosed with atrial fibrillation (AF). Thus, our goal was to build a predictive model of MB for new users of all oral anticoagulants (OAC) with AF.. We identified patients hospitalized for any cause and discharged alive in the community from 2011 to 2017 with a primary or secondary diagnosis of AF in Quebec's RAMQ and Med-Echo administrative databases. Cohort entry occurred at the first OAC claim. Patients were categorized according to OAC type. Outcomes were incident MB, gastrointestinal bleeding (GIB), non-GI extracranial bleeding (NGIB) and intracranial bleeding within 1 year of follow-up. Covariates included age, sex, co-morbidities (within 3 years before cohort entry) and medication use (within 2 weeks before cohort entry). We used logistic-LASSO and adaptive logistic-LASSO regressions to identify MB predictors among OAC users. Discrimination and calibration were assessed for each model and a global model was selected. Subgroup analyses were performed for MB subtypes and OAC types.. Our cohort consisted of 14,741 warfarin, 3,722 dabigatran, 6,722 rivaroxaban and 11,196 apixaban users aged 70-86 years old. The important MB predictors were age, prior MB and liver disease with ORs ranging from 1.37-1.64. The final model had a c-statistic of 0.63 (95% CI 0.60-0.65) with adequate calibration. The GIB and NGIB models had similar c-statistics of 0.65 (95% CI 0.63-0.66) and 0.67 (95% CI 0.64-0.70), respectively.. MB and MB subtype predictors were similar among DOAC and warfarin users. The predictors selected by our models and their discriminative potential are concordant with published data. Thus, these models can be useful tools for future pharmacoepidemiologic studies involving older oral anticoagulant users with AF.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Databases, Factual; Female; Gastrointestinal Hemorrhage; Hemorrhage; Hospitalization; Humans; Intracranial Hemorrhages; Male; Pyrazoles; Pyridones; Regression Analysis; Rivaroxaban; Warfarin

Our aim was to compare adverse drug reactions (ADRs) associated with direct-acting oral anticoagulants and vitamin K antagonists from the European EudraVigilance (EV) database. The EV database is the system for the analysis of information on suspected ADRs that are authorised, or being evaluated in clinical trials, in the European Economic Area. Registered ADRs (from the groups "Gastrointestinal disorders", "General disorders and administration site conditions", "Injury, poisoning and procedural complications", "Nervous system (NS) disorders" and "Vascular disorders") for apixaban, rivaroxaban, dabigatran and vitamin K antagonists (VKA) were collected by age group (< 65 years; 65-85 years and > 85 years) and by sex. The proportional reporting ratio (PRR) was used to compare ADRs in relation to the anticoagulants tested. A total of 274,693 ADRs were analysed. For gastrointestinal ADRs, patients treated with rivaroxaban and dabigatran (PRR 2.17 and 2.51, respectively) were at significantly higher risks than those treated with apixaban and VKA (PRR 1.27 and 1.47, respectively), while risks for vascular disorders were increased by all anticoagulants that were tested. Lastly, none of the anticoagulants significantly increased the risk of ADRs within the NS group. Rivaroxaban and dabigatran were associated with a significantly higher risk of gastrointestinal ADR than apixaban or VKA. All anticoagulants increased the risk of vascular pathology while none of them demonstrated significant increased risk of ADR to NS.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Dabigatran; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Female; Gastrointestinal Diseases; Humans; Male; Middle Aged; Pharmacovigilance; Pyrazoles; Pyridones; Rivaroxaban; Vitamin K; Young Adult

To address literature gaps on treatment with real-world evidence, this study compared effectiveness, safety, and cost outcomes in NVAF patients with coronary or peripheral artery disease (CAD, PAD) prescribed apixaban versus other oral anticoagulants. NVAF patients aged ≥65 years co-diagnosed with CAD/PAD initiating warfarin, apixaban, dabigatran, or rivaroxaban were selected from the US Medicare population (January 1, 2013 to September 30, 2015). Propensity score matching was used to match apixaban versus warfarin, dabigatran, and rivaroxaban cohorts. Cox models were used to evaluate the risk of stroke/systemic embolism (SE), major bleeding (MB), all-cause mortality, and a composite of stroke/myocardial infarction/all-cause mortality. Generalized linear and two-part models were used to compare stroke/SE, MB, and all-cause costs between cohorts. A total of 33,269 warfarin-apixaban, 9,335 dabigatran-apixaban, and 33,633 rivaroxaban-apixaban pairs were identified after matching. Compared with apixaban, stroke/SE risk was higher in warfarin (hazard ratio [HR]: 1.93; 95% confidence interval [CI]: 1.61 to 2.31), dabigatran (HR: 1.69; 95% CI: 1.18 to 2.43), and rivaroxaban (HR: 1.24; 95% CI: 1.01 to 1.51) patients. MB risk was higher in warfarin (HR: 1.67; 95% CI: 1.52 to 1.83), dabigatran (HR: 1.37; 95% CI: 1.13 to 1.68), and rivaroxaban (HR: 1.87; 95% CI: 1.71 to 2.05) patients vs apixaban. Stroke/SE- and MB-related medical costs per-patient per-month were higher in warfarin, dabigatran, and rivaroxaban patients versus apixaban. Total all-cause health care costs were higher in warfarin and rivaroxaban patients compared with apixaban patients. In conclusion, compared with apixaban, patients on dabigatran, rivaroxaban, or warfarin had a higher risk of stroke/SE, MB, and event-related costs.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cause of Death; Coronary Artery Disease; Dabigatran; Embolism; Female; Health Care Costs; Hemorrhage; Humans; Male; Mortality; Myocardial Infarction; Peripheral Arterial Disease; Propensity Score; Proportional Hazards Models; Pyrazoles; Pyridones; Rivaroxaban; Stroke; United States; Warfarin

Analysis of the pathogenesis of coronavirus infection caused SARS-CoV-2 indicates a significant impact of hemorheological disorders on its course and outcomes. It is known that chronic cardiovascular diseases are associated with the risk of severe course and lethal outcomes both in COVID-19 and other infectious diseases. Therefore, in each case it is necessary to study the interaction and mutual influence of different components of the treatment program prescribed to such patients.The purpose of this work was to evaluate the effect of coagulation activity on the course of a novel coronavirus infection (COVID-19) and to justify the management of comorbid patients having been received novel oral anticoagulants (NOACs) in previously selected doses according to indications in concomitant somatic diseases.. Total 76 cases of confirmed coronavirus infection in patients who had been received initial therapy on an outpatient basis were analyzed. 26 patients who received NOACs (rivaroxaban, apixaban, dabigatran) made up the main group and 50 - the comparison (control) group in which patients had not been administered any drugs that affect blood clotting until the episode of COVID-19. All patients have been prescribed therapy following the Provisional guidelines «Prevention, diagnosis and treatment of coronavirus infection (COVID-19)» (https://static-0.minzdrav.gov.ru/system/attachments/attaches/).. The number of hospitalizations was significantly fewer in the group of patients who had been received NOACs (19 vs. 66% in the control group). No deaths or cases of severe respiratory and/or renal failure were observed in the main group, while adverse outcomes were noted in 14% of patients who had not been administered these drugs.. Taking NOACs reduces the probability of severe course and adverse outcomes in the development of coronavirus infection caused by SARS-CoV-2, which indicates a significant contribution of coagulation mechanisms to the pathogenesis in COVID-19. There were no indications for drug replacement and correction of anticoagulant therapy regimens in patients who received adequate therapy with oral anticoagulants for treating a non-severe form of coronavirus infection in ambulatory patient settings.

Topics: Acetylcysteine; Aged; Aged, 80 and over; Anticoagulants; Antiviral Agents; Atrial Fibrillation; Azithromycin; Cohort Studies; Comorbidity; Coronary Disease; COVID-19; COVID-19 Drug Treatment; Dabigatran; Disseminated Intravascular Coagulation; Female; Humans; Hypertension; Indoles; Interferon alpha-2; Intracranial Arteriosclerosis; Male; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban; SARS-CoV-2; Severity of Illness Index; Survival Analysis

We report the cases of two patients who developed worsening behavioural and psychological symptoms of dementia (BPSD), coinciding with starting the factor Xa inhibitor direct oral anticoagulant medications apixaban and rivaroxaban, respectively. Both patients required detaining under the Mental Health Act. Their symptoms improved significantly, within 2 weeks, on switching to alternative anticoagulant therapies and they were both discharged from the acute psychiatric ward. Front-line staff should partake in postmarketing surveillance of medications, completing the Medicines and Healthcare products Regulatory Agency yellow cards for example (UK). There is increasing evidence for an aetiological role of cerebral mitochondrial dysfunction in neuropsychiatric disorders. Development of a rating scale of drugs that are potentially less toxic to cerebral mitochondria could inform national prescribing guidelines and enable safer treatments to be offered to older people, reducing the likely hood of them experiencing apparent BPSD.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Dabigatran; Dementia; Humans; Pyrazoles; Pyridones; Rivaroxaban

Diabetes mellitus is a common comorbidity of atrial fibrillation (AF), which can complicate the management of AF. The pharmacology of oral anticoagulants (OACs) have been implicated in pathogenesis of diabetes, but the relationship between different OACs and risk of diabetes remains unexamined. This study aimed to evaluate the risk of diabetes with use of different OACs in AF patients.. Population-based retrospective cohort study using an electronic healthcare database managed by the Hong Kong Hospital Authority. Patients newly diagnosed with AF from 2014 through 2018 and prescribed OACs were included and followed till December 31, 2019. Inverse probability of treatment weighting based on the propensity score (PS) is used to address potential bias due to nonrandomized allocation of treatment. The risks ofdiabetes were compared between different new OAC users using propensity score-weighted cumulative incidence differences (CID).. There were 13,688 new users of OACs (warfarin: n = 3454; apixaban: n = 3335; dabigatran: n = 4210; rivaroxaban: n = 2689). The mean age was 75.0 (SD, 11.2), and 6,550 (47.9%) were women. After a median follow-up of 0.93 years (interquartile range, 0.21-1.92 years), 698 incident diabetes cases were observed. In Cox-regression analysis, dabigatran use was significantly associated with reduced risk of diabetes when compared with warfarin use [HR 0.69 (95% CI 0.56-0.86; P < 0.001)], with statistically insignificant associations observed for use of apixaban and rivaroxaban. The corresponding adjusted CIDs at 2 years after treatment with apixaban, dabigatran, and rivaroxaban users when compared with warfarin were - 2.06% (95% CI - 4.08 to 0.16%); - 3.06% (95% CI - 4.79 to - 1.15%); and - 1.8% (- 3.62 to 0.23%). In head-to-head comparisons between women DOAC users, dabigatran was also associated with a lower risk of diabetes when compared with apixaban and rivaroxaban.. Among adults with AF receiving OACs, the use of dabigatran had the lowest risk of diabetes when compared with warfarin use.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Databases, Factual; Diabetes Mellitus; Factor Xa Inhibitors; Female; Hong Kong; Humans; Incidence; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Risk Assessment; Risk Factors; Rivaroxaban; Sex Factors; Time Factors; Treatment Outcome; Warfarin

Direct oral anticoagulants (DOACs) are increasingly used in place of warfarin, but evidence about their effectiveness and safety in patients with valvular atrial fibrillation (AF) remains limited.. To assess the effectiveness and safety of DOACs compared with warfarin in patients with valvular AF.. New-user retrospective propensity score-matched cohort study.. U.S.-based commercial health care database from 1 January 2010 to 30 June 2019.. Adults with valvular AF who were newly prescribed DOACs or warfarin.. The primary effectiveness outcome was a composite of ischemic stroke or systemic embolism. The primary safety outcome was a composite of intracranial or gastrointestinal bleeding.. Among a total of 56 336 patients with valvular AF matched on propensity score, use of DOACs (vs. warfarin) was associated with lower risk for ischemic stroke or systemic embolism (hazard ratio [HR], 0.64 [95% CI, 0.59 to 0.70]) and major bleeding events (HR, 0.67 [CI, 0.63 to 0.72]). The results for the effectiveness and safety outcomes remained consistent for apixaban (HRs, 0.54 [CI, 0.47 to 0.61] and 0.52 [CI, 0.47 to 0.57], respectively) and rivaroxaban (HRs, 0.74 [CI, 0.64 to 0.86] and 0.87 [CI, 0.79 to 0.96], respectively); with dabigatran, results were consistent for the major bleeding outcome (HR, 0.81 [CI, 0.68 to 0.97]) but not for effectiveness (HR, 1.03 [CI, 0.81 to 1.31]).. Relatively short follow-up; inability to ascertain disease severity.. In this comparative effectiveness study using practice-based claims data, patients with valvular AF who were new users of DOACs had lower risks for ischemic stroke or systemic embolism and major bleeding than new users of warfarin. These data may be used to guide risk-benefit discussions regarding anticoagulant choices for patients with valvular AF.. None.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Comparative Effectiveness Research; Dabigatran; Embolism; Female; Follow-Up Studies; Gastrointestinal Hemorrhage; Humans; Ischemic Stroke; Male; Propensity Score; Pyrazoles; Pyridones; Retrospective Studies; Risk Factors; Rivaroxaban; Treatment Outcome; Warfarin

The clinical use of factor VIII inhibitor bypassing activity (FEIBA) for factor Xa (FXa) inhibitor reversal is derived from small studies with notable variation in patient eligibility for use, dosage regimens, concurrent supportive care, and outcome measures. Consequently, additional effectiveness and safety data are warranted to expand the literature evaluating FEIBA for FXa inhibitor reversal.. This study sought to determine the incidence of observed effective hemostasis within 24 hours of post-FEIBA® administration as well as in-hospital and 30-day post-discharge incidences of thromboembolic event (TEE) and mortality between apixaban and rivaroxaban in the intracranial hemorrhage (ICH) and non-ICH populations.. This case series evaluated patients between January 1, 2014 through July 1, 2019 who received at least one FEIBA® dose for apixaban or rivaroxaban reversal secondary to acute ICH or non-ICH. Patient demographics, FEIBA® dosages, adjunct treatments, effectiveness, and safety outcomes were retrospectively collected from electronic medical record review. Modified hemostasis outcomes, adapted from criteria previously published by Sarode et al., TEE, and mortality between apixaban and rivaroxaban in the ICH and non-ICH populations were evaluated.. Among the 104 patients evaluated, 62 received apixaban and 42 rivaroxaban. Thirty apixaban and 25 rivaroxaban users experienced ICH, whereas 32 apixaban and 17 rivaroxaban users experienced non-ICH. Among the combined ICH and non-ICH populations, effective hemostasis occurred in 89%, TEE in 8%, and mortality in 13%. No statistically significant differences were observed within ICH and non-ICH populations receiving apixaban or rivaroxaban regarding effective hemostasis, TEE, or mortality.. The combined ICH and non-ICH overall rates of effective hemostasis, TEE, and mortality were comparable to preexisting studies of FEIBA for factor Xa inhibitor reversal. The limitations inherent to the study design warrant a randomized controlled trial with an active comparator to confirm these observations.

Topics: Aftercare; Blood Coagulation Factors; Hemorrhage; Humans; Patient Discharge; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban

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

Rivaroxaban is a commonly used anticoagulant agent for treatment and prevention of thromboembolism. There are case reports demonstrating an association between its use and drug-induced liver injury. However, this has not been reported in a patient who previously tolerated apixaban. An 88-year-old man presented to hospital with worsening lethargy, jaundice and vomiting. He had severely elevated liver transaminases, an abnormal coagulation profile and elevated bilirubin in keeping with acute liver injury. This is in the context of having had his anticoagulation medication switched from apixaban to rivaroxaban 2 weeks prior. The patient recovered well after cessation of rivaroxaban, suggesting that it was the likely offending agent. The mechanism of rivaroxaban-induced liver injury remains to be investigated. Drug-induced liver injury should be discussed and monitored for as a potential adverse reaction when commencing rivaroxaban, even if a patient has previously tolerated a drug of the same class.

Topics: Administration, Oral; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Humans; Liver Failure, Acute; Male; Pyrazoles; Pyridones; Rivaroxaban

Real-world evidence is accumulating to support the idea that there are differences among the direct oral anticoagulants (DOACs). The results of the study, discussed elsewhere in the NTvG, add to the growing body of evidence that while there is almost no difference in efficacy in prevention of the thromboembolic complications of non-valvular atrial fibrillation there are significant differences in safety. Apixaban is safer than rivaroxaban, with significantly less major bleeding, any bleeding or gastro-intestinal bleeding. Apixaban is probably the safest DOAC of the four available. These differences between DOACs with almost equal half-life are probably partly due to the differences in dosing interval: twice a day (BID) versus once a day (QD).

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Drug Administration Schedule; Female; Hemorrhage; Humans; Male; Pyrazoles; Pyridones; Rivaroxaban; Thromboembolism; Treatment Outcome

To evaluate the current interpretation of the lower doses of direct oral anticoagulants (DOAC) dabigatran, apixaban, edoxaban and rivaroxaban in nonvalvular atrial fibrillation.. A questionnaire of 14 statements to which the possible answers were fully agree/partially agree/partially disagree/fully disagree or yes/no was prepared within the board of the Italian Atherosclerosis, Thrombosis and Vascular Biology Study Group and forwarded to individual Italian physicians.. A total of 620 complete questionnaires were received from nearly all the Italian regions and physicians of various medical specialists, either enabled or not for the prescription of DOAC. A wide agreement was found as regards the pharmacological, as well as clinical consequences of the administration of the lower dose of factor-Xa inhibitors both in patients with and without clinical and/or laboratory criteria requiring dose reduction. Wide agreement was also found as regards the presence of moderate kidney insufficiency in selecting the dose of DOAC. Instead, more debated were issues regarding the proportionality between dabigatran dose and plasma concentration and selection of dabigatran dose, as well as the role of measuring drug plasma concentration and/or determine the anticoagulant activity of factor-Xa inhibitors when used at the lower dose.. The interpretation of the lower doses of DOAC in current Italian clinical practice appears largely correct and shared. Because of the persistence of some residual uncertainties, essentially regarding dabigatran, however, continuous educational effort still appears warranted.

Topics: Administration, Oral; Anticoagulants; Atherosclerosis; Atrial Fibrillation; Dabigatran; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Humans; Italy; Pyrazoles; Pyridines; Pyridones; Renal Insufficiency; Rivaroxaban; Surveys and Questionnaires; Thiazoles; Thrombosis; Treatment Outcome

Oral anticoagulants (OACs) pose a major bleeding risk, which may be increased or decreased by concomitant medications. To explore medications that affect the bleeding risk of OACs, we conducted a nested case-control study including 554 bleeding cases (warfarin, n = 327; direct OACs [DOACs], n = 227) and 1337 non-bleeding controls (warfarin, n = 814; DOACs, n = 523), using a Japanese health insurance database from January 2005 to June 2017. Major bleeding risk associated with exposure to concomitant medications within 30 d of the event/index date was evaluated, and adjusted odds ratios (aORs) were calculated using logistic regression analysis. Several antihypertensive drugs, such as amlodipine and bisoprolol, were associated with a decreased risk of bleeding (warfarin + amlodipine [aOR, 0.64; 95% confidence interval (CI): 0.41-0.98], DOACs + bisoprolol [aOR, 0.51; 95% CI, 0.33-0.80]). As hypertension is considered a significant risk factor for intracranial bleeding in antithrombotic therapy, antihypertensive drugs may suppress intracranial bleeding. In contrast, telmisartan, a widely used antihypertensive drug, was associated with an increased risk of bleeding [DOACs + telmisartan (aOR, 4.87; 95% CI, 1.84-12.91)]. Since telmisartan is an inhibitor of P-glycoprotein (P-gp), the elimination of rivaroxaban and apixaban, which are substrates of P-gp, is hindered, resulting in increased blood levels of both drugs, thereby increasing the risk of hemorrhage. In conclusion, antihypertensive drugs may improve the safety of OACs, and the pharmacokinetic-based drug interactions of DOACs must be considered.

Topics: Administration, Oral; Administrative Claims, Healthcare; Amlodipine; Anticoagulants; Antihypertensive Agents; ATP Binding Cassette Transporter, Subfamily B; Bisoprolol; Case-Control Studies; Drug Interactions; Female; Hemorrhage; Humans; Japan; Male; Middle Aged; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Telmisartan; Warfarin

Atorvastatin and direct oral factor Xa inhibitors (xabans) are frequently co-administrated in patients with atrial fibrillation (AF). However, no studies investigating the possibility of the pharmacologic interaction between these agents have been conducted. The aim of this prospective observational study was to determine the impact of atorvastatin therapy on anti-Xa activity in xabans-treated patients with AF. We enrolled 115 AF patients on long-term rivaroxaban (52 patients) and long-term apixaban (63 patients) therapy. Long-term atorvastatin (40 mg once daily) was administrated to 28 rivaroxaban-treated patients and to 28 apixaban-treated patients. Trough and peak samples were tested for anti-Xa activity with drug-specific anti-Xa chromogenic analysis. For rivaroxaban, there were no significant differences in trough activity (45.5 ± 39.5 ng/ml vs. 46.2 ± 30.1 ng/ml; p = .34) and peak anti-Xa activity (179.2 ± 108.8 ng/ml vs. 208.1 ± 104.1 ng/ml; p = .94) between atorvastatin-treated patients and those without atorvastatin. Similarly, atorvastatin did not impact the trough activity (127.7 ± 71.1 ng/ml vs. 100.8 ± 61.1 ng/ml; p = .12) or peak anti-Xa activity (213.8 ± 103.6 ng/ml vs. 179.3 ± 72.9 ng/ml; p = .14) among apixaban-treated patients with AF. This observational study did not show a significant impact of atorvastatin on trough and peak anti-Xa activity in xabans-treated patients with AF.

Topics: Aged; Aged, 80 and over; Atorvastatin; Atrial Fibrillation; Drug Interactions; Factor Xa Inhibitors; Female; Heart Failure; Hospitalization; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thrombosis

There have been reports of clinically relevant uterine bleeding events among women of reproductive age exposed to rivaroxaban.. The aim of this study was to compare the risk of severe abnormal uterine bleeding (SAUB) resulting in transfusion or surgical intervention among women on rivaroxaban versus apixaban, dabigatran and warfarin.. We conducted a retrospective cohort study in the FDA's Sentinel System (10/2010-09/2015) among females aged 18+ years with venous thromboembolism (VTE), or atrial flutter/fibrillation (AF) who newly initiated a direct oral anticoagulant (DOAC; rivaroxaban, apixaban, dabigatran) or warfarin. We followed women from dispensing date until the earliest of transfusion or surgery following vaginal bleeding, disenrollment, exposure or study end date, or recorded death. We estimated hazard ratios (HRs) using Cox proportional hazards regression via propensity score stratification. Four pairwise comparisons were conducted for each intervention.. Overall, there was an increased risk of surgical intervention with rivaroxaban when compared with dabigatran (HR 1.19; 95% CI 1.03-1.38), apixaban (1.23; 1.04-1.47), and warfarin (1.34; 1.22-1.47). No difference in risk for surgical intervention was observed for dabigatran-apixaban comparisons. Increased risk of transfusion was observed for rivaroxaban compared with dabigatran (1.49; 1.03-2.17) only. For patients with no gynecological history, rivaroxaban was associated with risk of surgical intervention compared with dabigatran (1.22; 1.05-1.42), apixaban (1.25; 1.04-1.49), and warfarin (1.36; 1.23-1.50).. Our study found increased SAUB risk with rivaroxaban use compared with other DOACs or warfarin. Increased risk with rivaroxaban was present among women without underlying gynecological conditions. Women on anticoagulant therapy should be aware of a risk of SAUB.

Topics: Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Humans; Male; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Uterine Hemorrhage; Warfarin

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

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

This study aimed to analyze associations between genetic variants and the occurrence of clinical outcomes in dabigatran, apixaban, and rivaroxaban users. This was a retrospective real-world study linking genotype data of three Finnish biobanks with national register data on drug dispensations and healthcare encounters. We investigated several single-nucleotide variants (SNVs) in the ABCG2, ABCB1, CES1, and CYP3A5 genes potentially associated with bleeding or thromboembolic events in direct oral anticoagulant (DOAC) users based on earlier research. We used Cox regression models to compare the incidence of clinical outcomes between carriers and noncarriers of the SNVs or haplotypes. In total, 1,806 patients on apixaban, dabigatran, or rivaroxaban were studied. The ABCB1 c.3435C>T (p.Ile1145=, rs1045642) SNV (hazard ratio (HR) 0.42, 95% confidence interval (CI), 0.18-0.98, P = 0.044) and 1236T-2677T-3435T (rs1128503-rs2032582-rs1045642) haplotype (HR 0.44, 95% CI, 0.20-0.95, P = 0.036) were associated with a reduced risk for thromboembolic outcomes, and the 1236C-2677G-3435C (HR 2.55, 95% CI, 1.03-6.36, P = 0.044) and 1236T-2677G-3435C (HR 5.88, 95% CI, 2.35-14.72, P < 0.001) haplotypes with an increased risk for thromboembolic outcomes in rivaroxaban users. The ABCB1 c.2482-2236G>A (rs4148738) SNV associated with a lower risk for bleeding events (HR 0.37, 95% CI, 0.16-0.89, P = 0.025) in apixaban users. ABCB1 variants are potential factors affecting thromboembolic events in rivaroxaban users and bleeding events in apixaban users. Studies with larger numbers of patients are warranted for comprehensive assessment of the pharmacogenetic associations of DOACs and their relevance for clinical practice.

Topics: Aged; Anticoagulants; Female; Genotype; Haplotypes; Hemorrhage; Humans; Male; Pharmacogenetics; Polymorphism, Single Nucleotide; Pyrazoles; Pyridones; Retrospective Studies; Risk; Rivaroxaban; Thromboembolism

Andexanet alfa (AnXa) was developed for anticoagulant effect reversal of direct factor Xa inhibitors (DXaI) (apixaban, rivaroxaban, edoxaban) in emergency situations. Regular anti-Xa assays are not suitable to evaluate anti-Xa activity after AnXa administration because of the high sample dilution resulting in the AnXa-DXaI dissociation which gives inaccurately high DXaI measured concentrations. This study aimed at developing dedicated STA-Liquid anti-Xa test set-ups for accurately measuring DXaI after reversal with AnXa.. Modified anti-Xa test set-ups, with reduced sample dilution, were developed to overcome regular assays limitations and to improve measured accuracy with results comparable to Portola microplate reference method used in clinical studies. Both regular and optimized assays were used to measure DXaI concentration in AnXa-containing samples. Quality controls, normal pooled plasma spiked with five DXaI and three AnXa concentrations, samples from DXaI-treated patients spiked with AnXa and ex vivo healthy volunteers having received both DXaI and AnXa were used.. The lower limit of quantitation of optimized anti-Xa assays was <10 ng/mL with CVs ≤10%. DXaI samples containing 300 ng/mL and 1 µmol/L AnXa resulted in DXaI residual concentrations of 29-72 ng/mL depending on the DXaI (76%-90% reversal), compared to 20-28 ng/mL with reference method (92%-94% reversal) and 135-165 ng/mL with regular assays (about 50% reversal).. Modified test set-ups are automated alternative to reference method with improved precision and reproducibility. They can be run in all laboratories where regular anti-Xa assays are performed using commercially available reagents.

Topics: Blood Coagulation; Blood Coagulation Tests; Factor Xa; Factor Xa Inhibitors; Humans; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiazoles

Background Rivaroxaban, apixaban and dabigatran are non-vitamin K antagonist oral anticoagulants (NOACs) that are widely used for treatment or prevention of venous thromboembolism and stroke in patients with atrial fibrillation. Objective To estimate and compare hemorrhagic events report of rivaroxaban, apixaban and dabigatran. Setting FDA Adverse Event Reporting System (FAERS) database. Methods The reporting odds ratio (ROR) was used to assess the signal of hemorrhagic events of different NOACs. Main outcome measure The overall hemorrhagic events and hemorrhagic events in different physiological systems. Results From January 1, 2014 to December 31, 2019, the total number of reports of hemorrhage related to rivaroxaban was 53,085, and the numbers of apixaban and dabigatran were 13,151 and 14,100 respectively. The overall ROR (95% CI) of hemorrhagic events reporting for rivaroxaban versus dabigatran and apixaban versus dabigatran were 1.58 (1.54-1.62) and 0.47 (0.46-0.48) respectively. The ROR (95% CI) for rivaroxaban versus dabigatran in gastrointestinal system, nervous system, renal and urinary system, skin and subcutaneous tissue, and eye system was 1.38 (1.34-1.42), 0.94 (0.90-0.98), 1.07 (1.01-1.13), 0.80 (0.70-0.90), and 1.38 (1.19-1.60) respectively. The RORs (95% CI) for apixaban versus dabigatran in gastrointestinal system, nervous system, renal and urinary system, skin and subcutaneous tissue, and eye system were 0.28 (0.27-0.29), 0.69 (0.66-0.73), 0.31 (0.29-0.34), 0.98 (0.86-1.12), and 1.18 (1.00-1.39), respectively. Conclusions Overall, we found a moderate signal of higher frequency of reporting hemorrhage in rivaroxban compared with dabigatran and decreased hemorrhagic event reporting in apixaban compared with dabigatran. While this potential signal has not been confirmed in clinical trials or observational studies, in clinical practice, attention should be paid to the risk of potential hemorrhage when the patients switch from apixaban to dabigatran or rivaroxban.

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

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

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

Topics: Anticoagulants; Dabigatran; Female; Humans; Incidence; Pyrazoles; Pyridones; Rivaroxaban; Uterine Hemorrhage; Venous Thromboembolism

The solid organ transplant community is slow to adopt the routine practice of using direct oral anticoagulants. Rivaroxaban and apixaban share common metabolic pathways with tacrolimus. This study aimed to clarify the impact of rivaroxaban/apixaban on tacrolimus troughs. Fifty solid organ transplant recipients with concomitant use of tacrolimus and rivaroxaban/apixaban were retrospectively assessed for changes in tacrolimus troughs and dose. Average dose-adjusted tacrolimus troughs and average tacrolimus total daily doses prior to and after rivaroxaban/apixaban initiation were compared. Subgroup analyses evaluating rivaroxaban and apixaban individually were performed. Rivaroxaban was prescribed to 18 recipients, and apixaban was prescribed to 32 recipients. Transplanted organs included kidney (n = 22), lung (n = 18), liver (n = 7), simultaneous pancreas and kidney (n = 1), and simultaneous kidney and liver (n = 2). The median doseadjusted tacrolimus trough and tacrolimus total daily dose prior to rivaroxaban/apixaban initiation was 2.15 ng/mL/mg (IQR 1.17, 3.37) and 4 mg (IQR 1.88, 6.25), respectively. The median dose-adjusted tacrolimus trough and tacrolimus total daily dose after rivaroxaban/apixaban initiation was 2.16 ng/mL/mg (IQR 1.24, 4.10) and 3.55 mg (IQR 1.5, 6.35), respectively. No significant difference was found between average dose-adjusted tacrolimus troughs or tacrolimus total daily doses before and after rivaroxaban/apixaban initiation or in the individual subgroup analyses for rivaroxaban/apixaban. It is unlikely that initiating rivaroxaban/apixaban affects tacrolimus troughs or requires tacrolimus dose adjustment. This study does not elucidate if tacrolimus affects rivaroxaban/apixaban pharmacokinetics or pharmacodynamics.

Topics: Humans; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Tacrolimus

Low dose direct acting oral anticoagulants (LDDOACS) were approved for elderly atrial Fibrillation (AF) patients with limited information. A retrospective analysis collecting baseline characteristics and outcomes in AF patients ≥ 80 prescribed LDDOAC or warfarin (W), from a multidisciplinary practice between 1/1/11 (First LDDOAC available) and 5/31/17 was conducted. From 9660 AF patients, 514 ≥ 80 received a LDDOAC and 422 W. A multivariable comparison found LDDOAC patients were older (p <0.001), had lower creatinine clearance (CrCl) (p = 0.006), used more anti-platelet drugs (p <0.001), and more often had new onset AF verses those prescribed W (p <0.001). There were no clinically significant differences among those patients receiving Dabigatran 75 mgs BID (D), Rivaroxaban 15mgs (R) or Apixaban 2.5mgs BID (A). Forty-eight and 50% of the patients remained on their LDDOAC or W for the observation period (p = 0.55). Stroke/systemic embolism (SSE) and CNS bleeds were 1.16 vs 2.22%/yr., (p = 0.143) and 1.46 vs 0.93%/yr., (p = 0.24). Mortality and major bleeds were 6.26 vs 1.67%/yr., and 12.3vs 3.77%/yr. (p <0.001). SSE were 1.1%/yr for D, R, and A (p = 0.94). CNS bleeds were 2.2 for D, 1.7 for R and 0.8%/yr. for A: p = 0.53. Major bleeding was: 14.3 for D, 14.1 for R and 9.1%/yr. for A, p = 0.048 (with A < R, p = 0.01). Mortality was 5.5 for D, 4.2 for R and 9.5% for A, p = 0.031. In conclusion, half the patients remained on their assigned anti-coagulant. SSE and intracranial bleed rates were similar and low. Major bleeds and deaths were different between groups emphasizing the need for prospective randomized trials in this growing population with AF.

Topics: Age Factors; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Embolism; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Intracranial Hemorrhages; Male; Multivariate Analysis; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Warfarin

Patients with atrial fibrillation (AF) on long-term direct oral anticoagulants (DOACs) may be at higher risk of bleeding because of higher anti-Xa or anti-IIa levels. However, there is no postmarketing study investigating these DOAC plasma levels at the time of bleeding. The aim of this study was to evaluate DOAC levels at the time of a bleeding emergency. We analyzed 5440 patients examined at our Emergency Department in from April 1, 2019, to September 30, 2019. During this period, we prospective identified 105 consecutive patients with bleeding while on long-term antithrombotic therapy; 49 patients had AF on DOACs. We compared DOAC levels in patients who bled against a control sample of 55 patients who tolerated long-term high dose DOAC therapy without any emergency. Samples of these patients were tested with drug-specific anti-Xa chromogenic analysis (rivaroxaban and apixaban) and with Hemoclot Thrombin Inhibitor assay (dabigatran). Dabigatran-treated patients who bled had significantly higher anti-IIa levels when compared with trough (261.4 ± 163.7 vs. 85.4 ± 57.2 ng/mL, P < 0.001) and peak samples of controls (261.4 ± 163.7 vs. 138.8 ± 78.7 ng/mL, P < 0.05). Similarly, there were significantly higher anti-Xa levels in rivaroxaban-treated and apixaban-treated patients with bleeding compared with trough control samples (rivaroxaban: 245.9 ± 150.2 vs. 52.5 ± 36.4 ng/mL, P <0.001 and apixaban: 311.8 ± 142.5 vs. 119.9 ± 81.7 ng/mL, P < 0.001), as well as in apixaban-treated patients when compared with peak control samples (311.8 ± 142.5 vs. 210.9 ± 88.7 ng/mL, P < 0.05). Finally, rivaroxaban anti-Xa levels in patients who bled tended to be higher compared with peak control samples (245.9 ± 150.2 vs. 177.6 ± 38.6 ng/mL, P = 0.13). This observational study showed a significant difference in anti-IIa and anti-Xa plasma levels in patients with AF with bleeding complications compared with those who tolerated long-term high-dose DOAC therapy without bleeding complications.

Topics: Aged; Aged, 80 and over; Antithrombins; Atrial Fibrillation; Case-Control Studies; Dabigatran; Drug Monitoring; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Pilot Projects; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban; Time Factors; Treatment Outcome

Given high recurrence risk after venous thromboembolism (VTE), guidelines recommend extended dose rivaroxaban (10 mg OD) or apixaban (2.5 mg BID) to be considered after 6 months of initial treatment. This study aimed to provide insight into clinical practice regarding the use of extended preventive treatment and to describe duration of the initial treatment. Linkage of nationwide health registers identified all in- and outpatients with VTE from April 2017 through 2018. Hazard ratios (HR) with 95% confidence intervals (CIs) were calculated adjusting for other VTE-related factors. The study included 6030 patients with VTE. Among rivaroxaban users, 2.2% (n = 113) received the extended 10-mg dose after mean 9.4 (SD 3.1) months of standard treatment. For apixaban, 4.7% (n = 40) received extended 2.5-mg dose after mean 8.0 months (SD 3.9). After adjustments, incident pulmonary embolism (HR 1.81 95% CI 1.12;2.91) and trauma/fracture (HR 1.42 95% CI 0.46;4.43) were associated with switching to extended dose, whereas patients with unprovoked VTE were less likely to receive the extended dose (HR 0.68 95% CI 0.30;1.55). Less than 3% of patients with incident VTE received extended treatment after initial standard treatment. Even though international guidelines suggest that the risk-benefit balance is in favour of extended VTE treatment, this was yet to be translated into clinical practice as of 2018. Studies using contemporary data are warranted to investigate routine clinical practice of extended treatment for VTE recurrence.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Cohort Studies; Female; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban; Treatment Outcome; Venous Thromboembolism

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Blood Specimen Collection; Dabigatran; Humans; Middle Aged; Preservation, Biological; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles

The role of differing levels of frailty in the choice of oral anticoagulants for older adults with atrial fibrillation (AF) is unclear.. To examine the outcomes of direct oral anticoagulants (DOACs) versus warfarin by frailty levels.. 1:1 propensity score-matched analysis of Medicare data, 2010 to 2017.. Community.. Medicare beneficiaries with AF who initiated use of dabigatran, rivaroxaban, apixaban, or warfarin.. Composite end point of death, ischemic stroke, or major bleeding by frailty levels, defined by a claims-based frailty index.. In the dabigatran-warfarin cohort (. Residual confounding and lack of clinical frailty assessment.. For older adults with AF, apixaban was associated with lower rates of adverse events across all frailty levels. Dabigatran and rivaroxaban were associated with lower event rates only among nonfrail patients.. National Institute on Aging.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Frail Elderly; Humans; Male; Massachusetts; Medicare; Propensity Score; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; United States; Warfarin

Thrombosis is the most common adverse event in patients with polycythemia vera (PV) and essential thrombocythemia (ET). Little is known about the use of nonvitamin K antagonist oral anticoagulants (NOACs) in patients with myeloproliferative neoplasms. We sought to evaluate the efficacy and safety of NOAC in a cohort of patients with PV and ET, who experienced venous thromboembolism (VTE). We enrolled 48 consecutive patients with PV (70.8%) and ET [median age 67.0 (interquartile range, 58.5-72.0) years], who experienced VTE. Patients received apixaban (39.6%), rivaroxaban (33.3%), or dabigatran (27.1%). During a median follow-up of 30 (interquartile range, 20.5-41.5) months, recurrent thrombotic events and bleeding were recorded. Four thrombotic events (3.3 per 100 patient-years) were reported. Three deep vein thrombosis episodes (2.5 per 100 patient-years) were experienced by 2 patients with PV, who received apixaban (5 mg bid) and dabigatran (150 mg bid), and 1 patient with ET, who received dabigatran (150 mg bid). One ischemic stroke occurred in a patient with PV on rivaroxaban (20 mg/d). There was 1 major bleeding (0.8 per 100 patient-years) in a patient with ET on dabigatran (150 mg bid) and 3 clinically relevant nonmajor bleeding (2.5 per 100 patient-years): 2 on rivaroxaban (20 mg/d) and 1 on apixaban (5 mg bid). We did not observe significant differences related to the type of NOAC. Three deaths (2.5 per 100 patient-years) unrelated to either VTE or bleeding were recorded. This study shows that NOACs may be effective and safe as secondary prevention of VTE in patients with myeloproliferative neoplasms.

Topics: Administration, Oral; Aged; Antithrombins; Dabigatran; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Polycythemia Vera; Pyrazoles; Pyridones; Recurrence; Risk Assessment; Risk Factors; Rivaroxaban; Secondary Prevention; Thrombocythemia, Essential; Time Factors; Treatment Outcome; Venous Thromboembolism

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

Anticoagulation with either a vitamin K antagonist or a direct oral anticoagulant may be associated with AKI. Our objective was to assess the risk of AKI among elderly individuals with atrial fibrillation newly prescribed a direct oral anticoagulant (dabigatran, rivaroxaban, or apixaban) versus warfarin.. Our population-based cohort study included 20,683 outpatients in Ontario, Canada, ≥66 years with atrial fibrillation who were prescribed warfarin, dabigatran, rivaroxaban, or apixaban between 2009 and 2017. Inverse probability of treatment weighting on the basis of derived propensity scores for the treatment with each direct oral anticoagulant was used to balance baseline characteristics among patients receiving each of the three direct oral anticoagulants compared with warfarin. Cox proportional hazards regression was performed in the weighted population to compare the association between the prescribed anticoagulant and the outcomes of interest. The exposure was an outpatient prescription of warfarin or one of the direct oral anticoagulants. The primary outcome was a hospital encounter with AKI, defined using Kidney Disease Improving Global Outcomes thresholds. Prespecified subgroup analyses were conducted by eGFR category and by the percentage of international normalized ratio measurements in range, a validated marker of anticoagulation control.. Each direct oral anticoagulant was associated with a significantly lower risk of AKI compared with warfarin (weighted hazard ratio, 0.65; 95% confidence interval, 0.53 to 0.80 for dabigatran; weighted hazard ratio, 0.85; 95% confidence interval, 0.73 to 0.98 for rivaroxaban; and weighted hazard ratio, 0.81; 95% confidence interval, 0.72 to 0.93 for apixaban). In the subgroup analysis, the lower risk of AKI associated with each direct oral anticoagulant was consistent across each eGFR strata. The risk of AKI was significantly lower among users of each of the direct oral anticoagulants compared with warfarin users who had a percentage of international normalized ratio measurements ≤56%.. Direct oral anticoagulants were associated with a lower risk of AKI compared with warfarin.

Topics: Acute Kidney Injury; Age Factors; Aged; Aged, 80 and over; Antithrombins; Atrial Fibrillation; Comorbidity; Dabigatran; Databases, Factual; Factor Xa Inhibitors; Female; Glomerular Filtration Rate; Humans; Male; Ontario; Pyrazoles; Pyridones; Risk Assessment; Risk Factors; Rivaroxaban; Time Factors; Treatment Outcome; Warfarin

To compare the bleeding risk in patients with gastrointestinal (GI) cancer with that in patients with non-GI cancer treated with anticoagulation for acute cancer-associated venous thromboembolism (Ca-VTE).. Consecutive patients with Ca-VTE seen at the Mayo Thrombophilia Clinic between March 1, 2013, and April 20, 2020, were observed prospectively to assess major bleeding and clinically relevant nonmajor bleeding (CRNMB).. In the group of 1392 patients with Ca-VTE, 499 (35.8%) had GI cancer including 272 with luminal GI cancer (lower GI, 208; upper GI, 64), 176 with pancreatic cancer, and 51 with hepatobiliary cancer. The rate of major bleeding and CRNMB in patients with GI cancer was similar to that in 893 (64.2%) patients with non-GI cancer treated with apixaban, rivaroxaban, or enoxaparin. Apixaban had a higher rate of major bleeding in luminal GI cancer compared with the non-GI cancer group (15.59 vs 3.26 per 100 person-years; P=.004) and compared with enoxaparin in patients with luminal GI cancer (15.59 vs 3.17; P=.04). Apixaban had a lower rate of CRNMB compared with rivaroxaban in patients with GI cancer (3.83 vs 9.40 per 100 person-years; P=.03). Patients treated with rivaroxaban in the luminal GI cancer group had a major bleeding rate similar to that of patients with non-GI cancer (2.04 vs 4.91 per 100 person-years; P=.37).. Apixaban has a higher rate of major bleeding in patients with luminal GI cancer compared with patients with non-GI cancer and compared with enoxaparin in patients with luminal GI cancer. Rivaroxaban shows no increased risk of major bleeding in patients with GI cancer or luminal GI cancer compared with patients with non-GI cancer.. ClinicalTrials.gov identifier: NCT03504007.

Topics: Enoxaparin; Factor Xa Inhibitors; Female; Gastrointestinal Neoplasms; Hemorrhage; Humans; Liver Neoplasms; Male; Middle Aged; Outcome and Process Assessment, Health Care; Pancreatic Neoplasms; Prospective Studies; Pulmonary Embolism; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Severity of Illness Index; United States; Venous Thrombosis

As an alternative to vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs) are increasingly prescribed in combination with riociguat in the treatment of chronic thromboembolic pulmonary hypertension (CTEPH). Pharmacokinetics of riociguat and DOACs are influenced by efflux transporters, such as P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). This work aimed to assess P-gp and BCRP-mediated drug-drug interactions of riociguat with DOACs using in vitro models. Bidirectional permeabilities of apixaban and rivaroxaban were investigated across MDCK-MDR1 and MDCK-BCRP models, in the absence and in the presence of increasing concentrations of riociguat (0.5-100 μm). Calculated efflux ratios were subsequently used to determine riociguat inhibition percentages and half maximal inhibitory concentration (IC50). P-gp-mediated efflux of apixaban and rivaroxaban was inhibited by 8% and 21%, respectively, in the presence of 100 μm riociguat. BCRP-mediated transport of apixaban and rivaroxaban was inhibited by 36% and 77%, respectively. IC50s of riociguat on MDCK-MDR1 and MDCK-BCRP models were higher than 100 μm for apixaban and higher than 100 μm and 46.5 μm for rivaroxaban, respectively. This work showed an in vitro inhibition of BCRP-mediated DOACs transport by riociguat. In vivo studies may be required to determine the clinical relevance of these transporter-mediated interactions.

Topics: Animals; Anticoagulants; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Biological Transport; Dogs; Drug Interactions; Inhibitory Concentration 50; Madin Darby Canine Kidney Cells; Pyrazoles; Pyridones; Pyrimidines; Rivaroxaban

Patients with cystic fibrosis (CF) and venous thromboembolism (VTE) pose therapeutic challenges including potential drug interactions between CF-related therapies and anticoagulants. Despite these challenges, there are no recommendations for VTE management specific to patients with CF. Our objective was to describe VTE treatment practices among Cystic Fibrosis Foundation (CFF)-accredited care centers and affiliate programs in the United States.. An online survey was distributed to CF center directors. The survey included questions regarding centers' demographics and posed a series of hypothetical clinical scenarios to gather centers' VTE treatment practices including choice of anticoagulant, dosing practices, duration decisions, and monitoring efforts. Descriptive statistics were utilized to summarize the survey results.. The survey response rate was 56.3%. Most centers reported treating zero to five VTE episodes per year. The following anticoagulants were used most often for VTE treatment: low-molecular-weight heparin (LMWH) (73.2%), apixaban (36.6%), warfarin (35.2%), rivaroxaban (33.8%), and unfractionated heparin (18.3%). On a scale of 0 to 100, the median confidence level in managing anticoagulant therapy was 50. Many centers expressed a desire for a CF-specific VTE treatment guideline. The most commonly cited challenging clinical situations were managing anticoagulant therapy complications (26.5%) and drug-drug interactions (21.3%). For common VTE scenarios, pediatric patients were most often treated with LMWH and warfarin, whereas adult patients were more often treated with apixaban or rivaroxaban.. Survey results indicated CF care centers find managing VTE in patients with CF challenging and indicated that a CF-specific VTE treatment guideline would be helpful.

Topics: Adult; Anticoagulants; Child; Cystic Fibrosis; Heparin; Humans; Practice Patterns, Physicians'; Pyrazoles; Pyridones; Rivaroxaban; Surveys and Questionnaires; Venous Thromboembolism; Warfarin

Rapidly available tests might be useful to measure the anticoagulant effect of direct oral anticoagulants (DOAs) in emergency situations as bleedings, surgery, or before thrombolysis. The aim of this study was to assess the effects of DOAs on global thromboelastometry (ROTEM). Coagulation parameters assessed at peak and trough in patients with non-valvular atrial fibrillation receiving apixaban, dabigatran or rivaroxaban at steady-state (patients) were compared to those of healthy volunteers (controls). Citrated blood samples were tested by ROTEM using diluted EXTEM assay, with and without the addition of an anti-FXa catcher, and using ECATEM-B, with and without the addition of an anti-FIIa catcher. Overall 30 patients (10 for each DOA) and 15 controls were included. The mean clotting time (CT) of patients at peak and trough were significantly higher compared to controls. The mean CT was significantly shortened after the addition of the anti-FXa catcher to apixaban (p = 0.005 for peak and p = 0.009 for trough) and to rivaroxaban samples (p = 0.005 for both peak and trough) and after the addition of anti-FIIa cather to dabigatran samples (p = 0.005 for both peak and trough). ROC curve analyses showed a good accuracy for CT and for CT/CT + catcher (CTc) in measuring dabigatran anticoagulant activity (AUC 1.000 and 0.993, respectively); for CT, CT/CTc and clot formation time (CFT)/CFT + catcher (CFTc) in measuring both apixaban activity (0.917, 0.880 and 0.880, respectively) and rivaroxaban activity (0.973, 0.987 and 0.860, respectively). In this study the use of ad-hoc designed reagents and catcher molecules was able to accurately identify DOAs activity at ROTEM.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Blood Coagulation Tests; Dabigatran; Female; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban; Thrombelastography

Direct oral anticoagulants (DOACs) are increasingly prescribed to elderly people, but the epidemiologic data for this population remains scarce. We compared the elderly population taking DOACs and those not taking DOACs (noDOAC).. We included individuals over 75 years old, affiliated to Mutualité Sociale Agricole of Burgundy (a French regional health insurance agency), who had been refunded for a prescribed DOAC between 1st and 30th September 2017. The DAOC group (DAOCG) and noDOAC group (noDOACG) were compared in terms of demographic conditions, registered chronic diseases (RCD), and number and types of prescribed drugs. In the DOACG, we compared the type of prescribing physician and laboratory monitoring for novel prescriptions (initial) and prescription refills (≥ 3 months).. Of the 19 798 included patients, 1518 (7.7%) were prescribed DAOCs and 18 280 (92.3%) were not. Mean and median age was 85 years in the 2 groups (DOACG and noDOACG). In the DOACG, there were more men (50% vs 40.2%), more RCD (88.9% vs 68.7%) and more drugs per prescription (6 ± 2.8 vs 5 ± 2.9) (All P < .01). The DOACG also took more antihypertensive drugs. The most commonly prescribed DOACs were apixaban (42.9%) followed by rivaroxaban (38.4%) and dabigatran (18.6%). Complete blood count, serum creatinine and coagulation function tests were requested for 69.4%, 75% and 22.2%, respectively, of patients prescribed DAOCs.. The DOACG had more RCD and drugs per prescription than the noDOACG; routine laboratory monitoring was insufficient. What's known Platelet aggregation inhibitors (low-dose) are recommended for secondary prevention of cardiovascular events in patients suffering from symptomatic atherosclerosis. The main risk of this treatment is bleeding. What's new A prescription for platelet aggregation inhibitors was found in 34% of geriatric inpatients in this prospective study. Compliance to guidelines was better for symptomatic peripheral artery disease than for primary prevention in accordance with recent publications. Geriatric comorbidities had no impact on the prescription of platelet aggregation inhibitors. Underuse of platelet aggregation inhibitors was observed in 11.3% of cases and overuse in 13.7% of cases.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Antihypertensive Agents; Blood Cell Count; Blood Coagulation Tests; Chronic Disease; Creatinine; Dabigatran; Drug Prescriptions; Female; France; Humans; Kidney Function Tests; Male; Platelet Aggregation Inhibitors; Practice Patterns, Physicians'; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban

Patients treated with direct Xa inhibitors may require urgent surgery. Administration of prothrombin complex concentrate (PCC) in this setting is common; however, it is based on limited experience in healthy volunteers.. To characterize the population receiving PCC for apixaban/rivaroxaban reversal prior to an urgent surgery and evaluate its efficacy and safety.. This was a retrospective study in 2 tertiary hospitals. Bleeding was evaluated based on surgical reports, hemoglobin drop, and the use of blood products or additional PCC during 48 h. Safety measures were thrombotic complications and 30-day mortality.. Sixty-two patients aged 80.7 ± 9 years, treated with apixaban (39.63%) or rivaroxaban (23.37%), received PCC before an urgent surgery/procedure. Most underwent abdominal operation (61%), orthopedic surgery (13%), or transhepatic cholecystostomy insertion (10%). Bleeding during surgery was reported in 3 patients (5%), no patient required additional PCC, and 16 patients (26%) received packed cells (median: 1 unit, range: 1-5). The 30-day mortality and thrombosis rates were 21% (n = 13) and 3% (n = 2), respectively. The cause of death was related to the primary disease, most commonly sepsis. No patient died due to bleeding/thrombosis.. Our results support the use of PCC to achieve hemostasis in patients treated with Xa inhibitors prior to an urgent surgery.

Topics: Academic Medical Centers; Aged; Aged, 80 and over; Atrial Fibrillation; Blood Coagulation Factors; Blood Component Transfusion; Blood Loss, Surgical; Emergencies; Factor Xa Inhibitors; Female; Hemostatics; Humans; Male; Postoperative Hemorrhage; Preoperative Care; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Surgical Procedures, Operative; Tertiary Care Centers; Thrombophilia; Thrombosis; Tranexamic Acid

Topics: Factor Xa; Factor Xa Inhibitors; Formularies, Hospital as Topic; Hemorrhage; Humans; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban

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

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

Topics: Aged; Aged, 80 and over; Blood Coagulation Factors; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban; Treatment Outcome

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

Accurate medication reconciliation in trauma patients is essential but difficult. Currently, there is no established clinical method of detecting direct oral anticoagulants (DOACs) in trauma patients. We hypothesized that a liquid chromatography-mass spectrometry (LCMS)-based assay can be used to accurately detect DOACs in trauma patients upon hospital arrival.. Plasma samples were collected from 356 patients who provided informed consent including 10 healthy controls, 19 known positive or negative controls, and 327 trauma patients older than 65 years who were evaluated at our large, urban level 1 trauma center. The assay methodology was developed in healthy and known controls to detect apixaban, rivaroxaban, and dabigatran using LCMS and then applied to 327 samples from trauma patients. Standard medication reconciliation processes in the electronic medical record documenting DOAC usage were compared with LCMS results to determine overall accuracy, sensitivity, specificity, and positive and negative predictive values (PPV, NPV) of the assay.. Of 356 patients, 39 (10.96%) were on DOACs: 21 were on apixaban, 14 on rivaroxaban, and 4 on dabigatran. The overall accuracy of the assay for detecting any DOAC was 98.60%, with a sensitivity of 94.87% and specificity of 99.05% (PPV, 92.50%; NPV, 99.37%). The assay detected apixaban with a sensitivity of 90.48% and specificity of 99.10% (PPV, 86.36%; NPV 99.40%). There were three false-positive results and two false-negative LCMS results for apixaban. Dabigatran and rivaroxaban were detected with 100% sensitivity and specificity.. This LCMS-based assay was highly accurate in detecting DOACs in trauma patients. Further studies need to confirm the clinical efficacy of this LCMS assay and its value for medication reconciliation in trauma patients.. Diagnostic Test, level III.

Topics: Administration, Oral; Aged; Anticoagulants; Chromatography, High Pressure Liquid; Dabigatran; Female; Healthy Volunteers; Humans; Male; Mass Spectrometry; Medication Reconciliation; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban; Sensitivity and Specificity; Wounds and Injuries

Clinical experience with using activated prothrombin complex concentrates (aPCCs) to reverse the effects of factor Xa inhibitors is limited.. Our objective was to assess the achievement of effective clinical hemostasis using aPCC in patients on chronic apixaban or rivaroxaban therapy presenting with major bleeding in whom a reversal agent is warranted. We also assessed the safety of the drug.. A retrospective medical records review was conducted at a tertiary referral medical center in the USA. Patients presenting with major bleeding while receiving apixaban or rivaroxaban and treated with aPCC were included. Clinical hemostasis was assessed using International Society of Thrombosis and Hemostasis Scientific and Standardization Subcommittee criteria.. A total of 35 patients were included in the study. The most common site of bleeding was intracerebral hemorrhage (ICH) (n = 18 [51.4%]), followed by gastrointestinal bleed (n = 10 [28.6%]). Clinical hemostasis was achieved in 24 (68.6%) patients; 11 patients (31.4%) did not achieve clinical hemostasis; nine of these patients had ICH. Seven of the patients who did not achieve hemostasis died during hospitalization. Three (8.6%) patients experienced thromboembolic events during hospitalization. In total, 21 (60%) patients were receiving concomitant medications that interact with anti-factor Xa inhibitors and can increase the risk of bleeding.. Our study suggests that aPCC could be an option in patients with major bleeding associated with apixaban or rivaroxaban. It may be an alternative for patients who need anticoagulation reversal if the specific antidote, andexanet alfa, is unavailable.

Topics: Aged; Antidotes; Blood Coagulation; Blood Coagulation Factors; Factor Xa Inhibitors; Female; Gastrointestinal Hemorrhage; Hemostasis; Humans; Intracranial Hemorrhages; Male; Outcome and Process Assessment, Health Care; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Survival Analysis; Thrombosis; United States

Topics: Anticoagulants; Humans; Neoplasms; Pyrazoles; Pyridones; Rivaroxaban; Venous Thromboembolism

Protein C (PC) deficiency results in dysregulated thrombin generation and increases thrombosis risk.. In order to investigate the potential effects of anticoagulant drugs in PC deficiency, we evaluated the pharmacodynamic effect of selective direct factor (F) IIa inhibitors (dabigatran and argatroban), selective direct FXa inhibitors (rivaroxaban and apixaban) and an indirect FXa/FIIa inhibitor (enoxaparin) in commercial PC-deficient plasma using thrombin generation and viscoelastometry assays modified to reflect PC anticoagulant activity.. Endogenous thrombin potential (ETP) and peak thrombin concentration (PTC) were increased in PC-deficient plasma but this corrected completely with PC concentrate. Inhibition of FIIa and FXa with the selective inhibitors also corrected the increased ETP and PTC but required high drug concentrations. There was sustained low-level thrombin generation in PC-deficient plasma with FXa inhibitors but not with FIIa inhibitors. Adding PC concentrate to PC-deficient plasma anticoagulated with dabigatran had little additional effect on ETP or PTC. In contrast, addition of even small quantities of PC concentrate to PC-deficient plasma anticoagulated with rivaroxaban further diminished ETP, primarily by abolishing sustained thrombin generation. In the viscoelastometry assay, the coagulation time was shortened and α-angle increased in PC-deficient plasma. These abnormalities reversed with both dabigatran and rivaroxaban.. The selective direct FXa and FIIa inhibitors at high concentrations both counteracted the abnormal thrombin generation and clot formation observed in PC-deficient plasma, but with qualitative differences in their effects.

Topics: Blood Coagulation Tests; Enoxaparin; Factor Xa Inhibitors; Humans; Plasma; Protein C; Prothrombin; Pyrazoles; Pyridones; Rivaroxaban; Thrombin

Despite controversies, direct oral anticoagulants (DOACs) are increasingly used in antiphospholipid syndrome (APS). We investigated the safety and efficacy of DOACs versus vitamin K antagonists (VKAs) in real-life consecutive APS patients.. In a cohort study of 176 APS patients, which included 82 subjects who preferred DOACs or had unstable anticoagulation with VKAs, we recorded venous thromboembolism (VTE), cerebrovascular ischemic events or myocardial infarction, along with major bleeding or clinically relevant non-major bleeding (CRNMB).. APS patients were followed for a median time of 51 (interquartile range 43-63) months. Patients on DOACs and those on VKAs were similar with regard to baseline characteristics. APS patients treated with DOACs had increased risk of recurrent thromboembolic events and recurrent VTE alone compared with those on VKAs (hazard ratio (HR) = 3.98, 95% confidence interval (CI): 1.54-10.28,. During long-term follow-up of real-life APS patients, DOACs are less effective and less safe as VKAs in the prevention of thromboembolism.

Topics: Adult; Antiphospholipid Syndrome; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban; Venous Thromboembolism; Vitamin K

Warfarin is prescribed to patients with atrial fibrillation (AF) for the prevention of cardioembolic complications. Whether warfarin adversely affects bone health is controversial. The availability of alternate direct oral anticoagulant (DOAC) options now make it possible to evaluate the comparative safety of warfarin in association with fracture risk.. To test the hypothesis that, among patients with nonvalvular AF, use of DOACs vs warfarin is associated with lower risk of incident fracture.. This comparative effectiveness cohort study used the MarketScan administrative claims databases to identify patients with nonvalvular AF and who were prescribed oral anticoagulants from January 1, 2010, through September 30, 2015. To reduce confounding, patients were matched on age, sex, CHA2DS2-VASc (congestive heart failure, hypertension, age [>65 years = 1 point; >75 years = 2 points], diabetes, and previous stroke/transient ischemic attack [2 points], vascular disease) score, and high-dimensional propensity scores. The final analysis included 167 275 patients with AF. Data were analyzed from February 27, 2019 to September 18, 2019.. Warfarin and DOACs (dabigatran etexilate, rivaroxaban, and apixaban).. Incident hip fracture, fracture requiring hospitalization, and all clinical fractures (identified using inpatient or outpatient claims) defined by International Classification of Diseases, Ninth Revision, Clinical Modification codes.. In the study population of 167 275 patients with AF (38.0% women and 62.0% men; mean [SD] age, 68.9 [12.5] years), a total of 817 hip fractures, 2013 hospitalized fractures, and 7294 total fractures occurred during a mean (SD) follow-up of 16.9 (13.7) months. In multivariable-adjusted, propensity score-matched Cox proportional hazards regression models, relative to new users of warfarin, new users of DOACs tended to be at lower risk of fractures requiring hospitalization (hazard ratio [HR], 0.87; 95% CI, 0.79-0.96) and all clinical fractures (HR, 0.93; 95% CI, 0.88-0.98), whereas the association with hip fractures (HR, 0.91; 95% CI, 0.78-1.07) was not statistically significant. When comparing individual DOACs with warfarin, the strongest findings were for apixaban (HR for hip fracture, 0.67 [95% CI, 0.45-0.98]; HR for fractures requiring hospitalization, 0.60 [95% CI, 0.47-0.78]; and HR for all clinical fractures, 0.86 [95% CI, 0.75-0.98]). In subgroup analyses, DOACs appeared more beneficial among patients with AF who also had a diagnosis of osteoporosis than among those without a diagnosis of osteoporosis.. In this real-world population of 167 275 patients with AF, use of DOACs-particularly apixaban-compared with warfarin use was associated with lower fracture risk. These associations were more pronounced among patients with a diagnosis of osteoporosis. Given the potential adverse effects of warfarin on bone health, these findings suggest that caution should be used when prescribing warfarin to patients with AF at high risk of fracture.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Comorbidity; Comparative Effectiveness Research; Dabigatran; Factor Xa Inhibitors; Female; Fractures, Bone; Hip Fractures; Hospitalization; Humans; Incidence; Male; Middle Aged; Osteoporosis; Proportional Hazards Models; Protective Factors; Pyrazoles; Pyridones; Rivaroxaban; Warfarin

Prevention of thromboembolic disease requires patients' adherence to the extended thromboprophylaxis scheme. Oral anticoagulants are expected to improve adherence as a result of their route of administration; however, this assumption is yet to be confirmed. The purpose of this study was to assess the impact of the route of administration and dosage regimen on the compliance to the prescription.. This prospective cohort study included hip and knee arthroplasty patients who received pharmacological extended thromboprophylaxis with one daily injection, one daily oral tablet, or two daily oral tablets. A telephonic questionnaire was applied 35 days after the day of the surgery. Patients who omitted one or more doses of medication during the follow-up period were classified as "non-adherent." Differences of adherence rates were assessed.. Five hundred and twenty patients were included: 153 received Apixaban (oral, twice a day), 155 Enoxaparin (injectable, once a day), and 212 Rivaroxaban (oral, once a day). Patients receiving oral once a day medication was more compliant compared with those who received an oral medication twice a day. Non-adherence rates were 3.2 and 9.2%, respectively (p = 0.033). No significant differences (p = 0.360) were found between oral once a day and injectable once a day medication.. The number of daily doses prescribed was related to adherence to extended chemical prophylaxis, while the route of administration did not seem to have a significant impact. Strategies to promote outpatient compliance must be implemented, especially when regimes including more than one daily dose are prescribed.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Dose-Response Relationship, Drug; Drug Administration Routes; Enoxaparin; Female; Hip Fractures; Humans; Injections, Subcutaneous; Male; Medication Adherence; Middle Aged; Osteoarthritis; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban; Venous Thromboembolism; Young Adult

Stroke prevention in elderly patients with atrial fibrillation (AF) can be challenging, requiring a balance between thromboembolism prevention and serious bleeding. Comparisons of nonvitamin K antagonist oral anticoagulants (NOACs) and warfarin in older adults at different age strata (65-74, 75-89, and ≥ 90 years of age) in the daily practice have not been well described, particularly in Asians. We aimed to assess the clinical outcomes of NOACs compared with warfarin for stroke prevention in elderly patients with AF.. From 2012 to 2015, 64,169 patients ≥ 65 years of age with AF who received at least one NOAC (dabigatran, rivaroxaban, or apixaban) or warfarin prescription were identified from the Taiwan National Health Insurance Research Database. The risks of ischemic stroke, intracranial hemorrhage (ICH), major bleeding, mortality, and composite adverse events were compared between NOACs and warfarin in all patients ≥ 65 years of age and, specifically, with different age strata (ie, 65-74, 75-89, ≥ 90 years).. Overall, NOACs were associated with a significantly lower risk of ischemic stroke (adjusted hazard ratio [aHR], 0.869; 95% CI, 0.812-0.931), ICH (aHR, 0.524; 95% CI, 0.456-0.601), major bleeding (aHR, 0.824; 95% CI, 0.776-0.875), mortality (aHR, 0.511; 95% CI, 0.491-0.532), and composite adverse events (aHR, 0.646; 95% CI, 0.625-0.667) than warfarin. There was heterogeneity in treatment effect for NOACs vs warfarin in different age strata, but the results still favored NOACs even among very older adults (≥ 90 years). The results were generally consistent with propensity matching analysis. The absolute risk difference and reductions in ICH and composite adverse events with NOAC use were even greater among older adults than warfarin.. Compared with warfarin, NOACs were associated with a significantly lower risk of adverse events, with heterogeneity in treatment effects among different age strata. Overall, the clear safety signal in favor of NOACs over warfarin was evident irrespective of age strata, being most marked in very older adults.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Cohort Studies; Dabigatran; Factor Xa Inhibitors; Female; Humans; Male; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Taiwan; Warfarin

Topics: Anticoagulants; Chromatography, High Pressure Liquid; Dabigatran; Graphite; Humans; Limit of Detection; Magnetite Nanoparticles; Nanocomposites; Plasma; Pyrazoles; Pyridones; Rivaroxaban; Solid Phase Extraction

Direct oral anticoagulants (DOACs) have been proven non-inferior or superior to warfarin in preventing stroke and systemic embolism, with a lower risk of major hemorrhage, in patients with non-valvular atrial fibrillation (NVAF). We sought to investigate whether effectiveness and safety differs among apixaban, rivaroxaban and dabigatran.. Patients with newly initiated DOAC treatment were identified from the Swedish anticoagulation quality registry, ranging from January 1, 2013 to December 31, 2015. Patients were assigned to apixaban, dabigatran or rivaroxaban cohorts based on initiated DOAC and dose (standard or reduced). Baseline characteristics and endpoints were retrieved from validated Swedish quality registers and the National Patient Registry. Cohorts were matched using full optimal matching and directly compared.. A total of 25,843 NVAF patients were included. Patients treated with standard dose apixaban or dabigatran had lower risk of major bleeding than patients treated with rivaroxaban, HR 0.69 (95% CI 0.54-0.88) and HR 0.64 (95% CI 0.48-0.87). Regarding reduced dose, patients treated with apixaban had lower risk of major bleeding than those treated with dabigatran or rivaroxaban, HR 0.62 (95% CI 0.44-0.88) and HR 0.45 (95% CI 0.33-0.61). In reduced dose, patients treated with dabigatran had the lowest all-cause mortality. No differences in effectiveness were found.. In this large real-world NVAF cohort, direct comparisons show a favorable bleeding risk profile for dabigatran and apixaban in standard dose, and for apixaban in reduced dose. No differences in effectiveness were found. This study confirms previous indirect DOAC comparisons. Further studies are needed.

Topics: Anticoagulants; Atrial Fibrillation; Dabigatran; Humans; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke

Clinical application of rivaroxaban and apixaban does not require therapeutic monitoring. Commercial anti-activated factor X (anti-FXa) inhibition methods for all anti-FXa drugs are based on the same principle, so there are attempts to evaluate potential clinical application of heparin-calibrated anti-FXa assay as an alternative method for direct FXa inhibitors. We aimed to evaluate relationship between anti-FXa methods calibrated with low molecular weight heparin (LMWH) and with drug specific calibrators, and to determine whether commercial LMWH anti-FXa assay can be used to exclude the presence of clinically relevant concentrations of rivaroxaban and apixaban.. Low molecular weight heparin calibrated reagent (Siemens Healthineers, Marburg, Germany) was used for anti-FXa activity measurement. Innovance heparin (Siemens Healthineers, Marburg, Germany) calibrated with rivaroxaban and apixaban calibrators (Hyphen BioMed, Neuville-sur-Oise, France) was used for quantitative determination of FXa inhibitors.. Analysis showed good agreement between LMWH calibrated and rivaroxaban calibrated activity (κ = 0.76) and very good agreement with apixaban calibrated anti-Xa activity (κ = 0.82), respectively. Low molecular weight heparin anti-FXa activity cut-off values of 0.05 IU/mL and 0.1 IU/mL are suitable for excluding the presence of clinically relevant concentrations (< 30 ng/mL) of rivaroxaban and apixaban, respectively. Concentrations above 300 ng/mL exceeded upper measurement range for LMWH anti-FXa assay and cannot be determined by this method.. Low molecular weight heparin anti-FXa assay can be used in emergency clinical conditions for ruling out the presence of clinically relevant concentrations of rivaroxaban and apixaban. However, use of LMWH anti-FXa assay is not appropriate for their quantitative determination as an interchangeable method.

Topics: Anticoagulants; Area Under Curve; Blood Coagulation Tests; Calibration; Chromogenic Compounds; Factor Xa; Factor Xa Inhibitors; Heparin, Low-Molecular-Weight; Humans; Pyrazoles; Pyridones; Rivaroxaban; ROC Curve

The study objective was to evaluate the safety and effectiveness of dabigatran and other direct oral anticoagulants (DOACs) compared with warfarin among patients with nonvalvular atrial fibrillation using a prospective monitoring program. We implemented a cohort design with propensity score matching to compare initiators of DOACs and warfarin between 2010 and 2015 in two US healthcare databases. Proportional hazards regression was used to estimate hazard ratios (HRs) for stroke and major bleeding. The final analyses included 29,448 dabigatran, 35,520 rivaroxaban, and 19,588 apixaban initiators, matched to warfarin initiators. The pooled HR for stroke was 0.75 (95% confidence interval (CI) 0.58-0.98) for dabigatran, 0.77 (95% CI 0.61-0.98) for rivaroxaban, and 0.69 (95% CI 0.50-0.96) for apixaban, consistent with findings from randomized trials. For major hemorrhage, the HRs were 0.72 (95% CI 0.65-0.80), 1.02 (95% CI 0.94-1.12), and 0.56 (95% CI 0.49-0.64), respectively, showing a decreased risk of major bleeding for both dabigatran and apixaban, as compared with trial evidence.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Cohort Studies; Dabigatran; Female; Hemorrhage; Humans; Longitudinal Studies; Male; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Warfarin; Young Adult

In 2018, the FDA approved andexanet alfa for the reversal of life-threatening hemorrhages in patients anticoagulated with apixaban or rivaroxaban. Yet, cost-effective factor Xa inhibitor reversal remains controversial. The objective of this study was to describe real world utilization of andexanet alfa.. This was a retrospective case series of patients receiving andexanet alfa between July 28, 2018 and April 29, 2019 at a large academic health system. Baseline demographics, anticoagulant type and reversal, as well as brain imaging were collected. Primary endpoints were stability of hematoma for intracranial hemorrhage (ICH), and hemostatic effectiveness for patients undergoing surgical procedures. Secondary endpoints were thromboembolism and 30 day mortality.. Of the 25 patients evaluated, 13 received andexanet alfa for ICH. Eleven of the 13 had follow-up imaging available and stability was observed in 90.9%. Three patients received andexanet alfa for reversal prior to surgical procedures, and 100% hemostatic effectiveness was achieved. Nine patients received andexanet alfa for reversal of extracranial bleeding, including gastrointestinal bleed (n=4). There were no thrombotic events in our cohort, and 30 day mortality was 24%. Sixty-four percent of patients would have met exclusion criteria for the ANNEXA-4 trial.. This is the largest series to date describing real-world utilization of andexanet alfa. Our series showed hemostatic efficacy in 90.9% of patients with ICH, and 100% in patients undergoing surgical procedures. There were no thrombotic complications. Yet, larger and comparative studies are needed to clarify the optimal agent and patient selection for reversal of factor Xa inhibitors.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Factor Xa; Gastrointestinal Hemorrhage; Hemorrhage; Hemostatics; Humans; Intracranial Hemorrhages; Male; Middle Aged; Pyrazoles; Pyridones; Recombinant Proteins; Retrospective Studies; Rivaroxaban; Surgical Procedures, Operative; Treatment Outcome

Topics: Administration, Oral; Anticoagulants; Blood Volume; Chromatography, Liquid; Dabigatran; Dried Blood Spot Testing; Humans; Pyrazoles; Pyridones; Rivaroxaban; Tandem Mass Spectrometry; Vitamin K

Background Warfarin, a vitamin K antagonist, has been shown to affect bone mineral density and cause osteoporosis. However, studies investigating the relationship between non-vitamin K antagonist oral anticoagulants (NOACs) and osteoporosis are limited. We thus compared the risk of osteoporosis in patients with atrial fibrillation treated with either NOACs or warfarin. Methods and Results This nationwide, retrospective cohort study used Taiwan's National Health Insurance Research Database. All adult patients in Taiwan who were newly diagnosed with atrial fibrillation and treated with NOACs or warfarin between January 2012 and December 2015 were included and classified into their respective cohorts. Patients who received NOACs were subcategorized into the rivaroxaban, dabigatran, and apixaban subgroups. Propensity score matching was performed for each head-to-head comparison. Adjusted hazard ratios (aHRs) for the risk of osteoporosis were calculated using Cox proportional hazards regression models, with adjustment for confounders. Overall, 17 008 patients were included, with 8504 in each cohort. NOACs were associated with a lower osteoporosis risk than warfarin (aHR=0.82; 95% CI=0.68-0.97). A subgroup effect of treatment duration was identified (namely, the lower osteoporosis risk with NOAC compared with warfarin became stronger in those with longer treatment duration [

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Databases, Factual; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Osteoporosis; Pyrazoles; Pyridones; Retrospective Studies; Risk Assessment; Risk Factors; Rivaroxaban; Taiwan; Treatment Outcome; Warfarin

The use of direct oral anticoagulants for stroke prevention in atrial fibrillation continues to rise. Certain populations may be at higher risk for increased drug exposure and adverse events. Pharmacokinetic studies suggest increased exposure of rivaroxaban and apixaban with combined P-gp and moderate CYP3A4 inhibitors but the clinical relevance of this is unknown. This retrospective cohort study included patients receiving rivaroxaban or apixaban from January 1, 2012 to December 31, 2016 with a moderate inhibitor (amiodarone, dronedarone, diltiazem, verapamil) for at least 3 months in the drug-drug interaction (DDI) group. Propensity matching was used to identify similar control patients without the presence of the DDI. The primary outcome was a time to event analysis of any bleeding episode as defined by the International Society of Thrombosis and Hemostasis. After propensity matching, 213 patients with similar baseline characteristics were included in each group. The mean CHA2DS2-VASc score was 3.0 and median duration of follow-up was 1.45 years. The primary outcome occurred in 26.4% of patients in the DDI group and 18.4% in the control group (hazard ratio 1.8, 95% confidence interval [CI] 1.19 to 2.73; p-value = 0.006). There was no difference in bleeding rates based on type of inhibitor. Use of a combined P-gp and moderate CYP3A4 inhibitor with rivaroxaban or apixaban increased bleeding risk compared to patients without the DDI in this real world, retrospective study. Analysis in a larger patient population is needed to confirm these findings.

Topics: Aged; Aged, 80 and over; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban

We sought to evaluate the effectiveness and safety of rivaroxaban vs apixaban in non-valvular atrial fibrillation (NVAF) patients with end-stage renal disease (ESRD) and/or receiving dialysis in routine practice.. Using US MarketScan claims data from January 1, 2014, to December 31, 2017, we identified new-users of rivaroxaban or apixaban during 2015 with at least 12 months of insurance coverage prior to oral anticoagulant (OAC) initiation. Differences in baseline covariates between cohorts were adjusted using inverse probability-of-treatment weighting based on propensity scores. Patients were followed for stroke or systemic embolism (SSE) or major bleeding hospitalizations. Cox proportion hazards regression was used to compare rivaroxaban and apixaban. Analyses stratified by age, sex, CHA2DS2-VASc score, prior stroke, prior bleed, diabetes, and reduced OAC dose were performed.. We identified 787 rivaroxaban and 1836 apixaban users. Median (25, 75% range) age = 70 (61, 79), CHA2DS2-VASc score = 3 (2, 4), and follow-up = 0.87 (0.38, 1.56) years. No differences in the risks of SSE (HR = 1.18, 95% CI = 0.53-2.63), ischemic stroke (HR = 1.12, 95%CI = 0.45-2.76), or major bleeding (HR = 1.00, 95% CI = 0.63-1.58) were observed. No significant interactions were observed upon subgroup analysis.. In NVAF patients with ESRD and/or receiving dialysis, rivaroxaban and apixaban were associated with similar risks of SSE and major bleeding.

Topics: Adult; Aged; Aged, 80 and over; Atrial Fibrillation; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Pyrazoles; Pyridones; Renal Dialysis; Retrospective Studies; Rivaroxaban

The aim of this study was to compare the risk of stroke or systemic embolism (SE) and major bleeding in patients with atrial fibrillation (AF) using dabigatran, rivaroxaban, and apixaban in routine clinical practice.. Using nationwide registries in Norway from January 2013 to December 2017, we established a cohort of 52 476 new users of non-vitamin K antagonist oral anticoagulants (NOACs) with AF. Users of individual NOACs were matched 1:1 on the propensity score to create three pairwise-matched cohorts: dabigatran vs. rivaroxaban (20 504 patients), dabigatran vs. apixaban (20 826 patients), and rivaroxaban vs. apixaban (27 398 patients). Hazard ratios (HRs) for the risk of stroke or SE and major bleeding were estimated. In the propensity-matched comparisons of the risk of stroke or SE, the HRs were 0.88 [95% confidence interval (CI) 0.76-1.02] for dabigatran vs. rivaroxaban, 0.88 (95% CI 0.75-1.02) for dabigatran vs. apixaban, and 1.00 (95% CI 0.89-1.14) for apixaban vs. rivaroxaban. For the risk of major bleeding, the HRs were 0.75 (95% CI 0.64-0.88) for dabigatran vs. rivaroxaban, 1.03 (95% CI 0.85-1.24) for dabigatran vs. apixaban, and 0.79 (95% CI 0.68-0.91) for apixaban vs. rivaroxaban.. In this nationwide study of patients with AF in Norway, we found no statistically significant differences in risk of stroke or SE in propensity-matched comparisons between dabigatran, rivaroxaban, and apixaban. However, dabigatran and apixaban were both associated with significantly lower risk of major bleeding compared with rivaroxaban.

Topics: Aged; Aged, 80 and over; Antithrombins; Atrial Fibrillation; Dabigatran; Databases, Factual; Embolism; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Incidence; Male; Middle Aged; Norway; Patient Safety; Pyrazoles; Pyridones; Registries; Risk Assessment; Risk Factors; Rivaroxaban; Stroke; Time Factors; Treatment Outcome

The present study aimed at describing (i) the characteristics of non-valvular atrial fibrillation (NVAF) patients newly treated with oral anticoagulants (vitamin K antagonists [VKA] or new oral anticoagulants [NOAC]), and (ii) their persistence to treatment assigned, clinical outcomes (bleeding and thromboembolic events) and mortality.. This study was conducted using administrative databases of an Italian Local Health Unit. All adult patients (aged ≥18 years) with NVAF and naïve to VKA (warfarin) or NOAC (rivaroxaban, apixaban, dabigatran) were included between January 1, 2014 and June 30, 2015. Propensity score matching was performed to check for confounding effects. Included patients were characterized for comorbidities, CHA2DS2-VASc and HAS-BLED score, antiplatelet drug use and followed up for at least 12 months to assess persistence to treatment and incidence of clinical outcomes.. A total of 970 NVAF patients newly treated with oral anticoagulants were included; 595 (61.3%) received VKA and 375 (38.7%) NOAC. VKA naïve patients had a lower low and intermediate score for HAS-BLED and CHA2DS2-VASc compared to NOAC patients. Overall, 80.6% of naïve NAO patients and 73.4% of naïve AVK patients were persistent to treatment. Incidence of bleeding events was slightly higher in VKA patients (3.13/100 persons year) compared to NOAC patients (2.73/100 persons years), as well as incidence of thromboembolic events (3.48/100 persons year and 2.18/100 persons year, respectively). After propensity score matching no differences were observed.. The majority of NVAF patients newly treated with oral anticoagulants received VKA-based therapy. Incidence of bleeding and thromboembolic events was slightly higher in VKA patients compared to NOAC patients.

Topics: Administration, Oral; Aged; Anticoagulants; Antithrombins; Atrial Fibrillation; Cause of Death; Comorbidity; Dabigatran; Databases, Factual; Female; Hemorrhage; Humans; Male; Medication Adherence; Platelet Aggregation Inhibitors; Propensity Score; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Thromboembolism; Warfarin

Studies on the use of direct oral anticoagulants (DOACs) in obese patients are limited. Current guidelines advise against DOAC use in patients with a body weight more than 120 kg or body mass index higher than 40 kg/m. Retrospective matched cohort study.. Integrated delivery system of 40 academic, community, and specialty hospitals.. A total of 1840 adults with a primary admission diagnosis of acute VTE who received a DOAC (apixaban, dabigatran, or rivaroxaban [632 patients] or warfarin [1208 patients]) while hospitalized between January 1, 2011, and October 1, 2015, and who had a body weight more than 100 kg and less than 300 kg, were included. Patients in the warfarin group were matched in a 2:1 ratio to patients who received a DOAC based on history of VTE, chronic kidney disease, race, and age.. The primary outcome was recurrence of VTE within 12 months of the index admission date. Secondary outcomes included occurrence of pulmonary embolism (PE) and deep vein thrombosis (DVT) events separately within the study time frame, as well as bleeding within 12 months of the index admission date. No significant difference in the recurrence of VTE was observed between patients who received a DOAC compared with those who received warfarin (6.5% vs 6.4%, p=0.93). Likewise, no significant differences in the occurrence of PE and DVT were seen between the DOAC- and warfarin-treated patients (3.7% vs 3.8%, p=0.94, and 3% vs 3.5%, p=0.56, respectively). Bleeding occurred in 1.7% and 1.2% of patients in the DOAC and warfarin groups, respectively (p=0.31).. To our knowledge, this is the largest clinical study to date showing that patients with obesity can be treated effectively and safely with a DOAC compared with warfarin for acute VTE. Thus DOACs should be considered a reasonable alternative to warfarin for treatment of acute VTE in obese patients.

Topics: Administration, Oral; Aged; Anticoagulants; Cohort Studies; Dabigatran; Female; Humans; Male; Middle Aged; Obesity, Morbid; Pulmonary Embolism; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Treatment Outcome; Venous Thromboembolism; Warfarin

Direct oral anticoagulants (DOACs) have been commonly used for the treatment of venous thromboembolism and for the prevention of stroke in patients with atrial fibrillation. Despite not being initially recommended, monitoring DOACs plasma concentrations is now recognized as essential in emergency situations and in special populations. Moreover, the inter-individual variability found in real studies as well as the high reported non-adherence are corroborating the importance of determining the individual relationship between administered doses, plasma concentrations and pharmacological effects. Therefore, accurate but user-friendly bioanalytical techniques are required to monitor DOACs plasma concentrations in routine clinical practice and phase IV clinical trials. Herein, a fast and simple high performance liquid chromatography (HPLC) method coupled to diode array detection (DAD) was developed, validated and applied to quantify the four currently marketed DOACs (apixaban, edoxaban, dabigatran and rivaroxaban). Sample preparation was performed by solid phase extraction followed by evaporation and concentration of the analytes. Chromatographic separation was accomplished within 6 min on a reversed-phase column (octadecyl-silica packing material; 55 mm × 4 mm, 3 μm particle size), applying a mobile phase composed of an aqueous solution of formic acid (0.1 %, v/v) and acetonitrile, pumped with a gradient elution at 30 °C. The proposed method was linear (r

Topics: Anticoagulants; Chromatography, High Pressure Liquid; Dabigatran; Humans; Plasma; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Solid Phase Extraction; Spectrophotometry; Thiazoles

The anticoagulant actions of oral direct factor Xa (FXa) inhibitors can be inferred from their observed plasma concentrations; however, the steady-state pharmacokinetics (PK) of different FXa inhibitors have not been compared in clinically.. The sensitivity of the rivaroxaban, apixaban, and edoxaban in the STA-Liquid Anti-FXa assay were compared, and the anti-FXa plasma concentrations were measured for PK assessments. Nonlinear mixed-effects modeling was used to assess population PK in 329 patients with nonvalvular atrial fibrillation or venous thromboembolism. Patients were followed up for an average of 3.6 years.. Sensitivity was similar among the three drugs in this assay, which could directly compare plasma concentrations instead of anti-FXa activities. Overall exposure was greatest in 5 mg BID apixaban relative to other drugs (p < 0.001). The geometric mean AUC for the 0 to 24-h interval was 4550 ng h/mL for apixaban, 2710 ng h/mL for 15 mg QD rivaroxaban, and 1290 ng h/mL for 60 mg QD edoxaban. The PKs of 2.5 mg BID apixaban or 15 mg QD rivaroxaban were associated with hemorrhagic events.. Apixaban was associated with greater exposure, higher trough concentrations in plasma compared with rivaroxaban or edoxaban. Furthermore, a higher plasma concentration may partially predict hemorrhagic events.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Blood Coagulation Tests; Chromatography, Liquid; Factor Xa; Factor Xa Inhibitors; Female; Humans; Male; Prospective Studies; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Tandem Mass Spectrometry; Thiazoles; Venous Thromboembolism

With increasing use of direct oral anticoagulants (DOACs) and availability of new reversal agents, the risk of traumatic intracranial hemorrhage (tICH) requires better understanding. We compared hemorrhage expansion rates, mortality, and morbidity following tICH in patients treated with vitamin k antagonists (VKA: warfarin) and DOACs (apixaban, rivaroxaban, dabigatran).. Retrospective chart review of patients from 2010 to 2017 was performed to identify patients with imaging diagnosis of acute traumatic intraparenchymal, subdural, subarachnoid, and epidural hemorrhage with preadmission use of DOACs or VKAs. We identified 39 patients on DOACs and 97 patients on VKAs. Demographic information, comorbidities, hemorrhage size, and expansion over time, as well as discharge disposition and Glasgow Outcome Scale (GOS) were collected. Primary outcome was development of new or enlargement of tICH within the first 48 h of initial CT imaging.. Of 136 patients with mean (SD) age 78.7 (13.2) years, most common tICH subtype was subdural hematoma (N = 102/136; 75%), and most common mechanism was a fall (N = 130/136; 95.6%). Majority of patients in the DOAC group did not receive reversal agents (66.7%). Hemorrhage expansion or new hemorrhage occurred in 11.1% in DOAC group vs. 14.6% in VKA group (p = 0.77) at a median of 8 and 11 h from initial ED admission, respectively (p = 0.82). Patients in the DOAC group compared to VKA group had higher median discharge GOS (4 vs. 3 respectively, p = 0.03), higher percentage of patients with good outcome (GOS 4-5, 66.7% vs. 40.2% respectively, p = 0.005), and higher rate of discharge to home or rehabilitation (p = 0.04).. We report anticoagulation-associated tICH outcomes predominantly due to fall-related subdural hematomas. Patients on DOACs had lower tICH expansion rates although not statistically significantly different from VKA-treated patients. DOAC-treated patients had favorable outcomes versus VKA group following tICH despite low use of reversal strategies. DOAC use may be a safer alternative to VKA in patients at risk of traumatic brain hemorrhage.

Topics: Accidental Falls; Aged; Aged, 80 and over; Anticoagulants; Antifibrinolytic Agents; Antithrombins; Blood Coagulation Factors; Coagulants; Dabigatran; Disease Progression; Factor Xa Inhibitors; Female; Glasgow Outcome Scale; Humans; Intracranial Hemorrhage, Traumatic; Length of Stay; Male; Middle Aged; Mortality; Neurosurgical Procedures; Plasma; Platelet Transfusion; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Rivaroxaban; Thiazoles; Vitamin K; Warfarin

Pharmacokinetic studies and therapeutic drug monitoring of anticoagulants require a simple, rapid, and reliable analytical method for monitoring plasma concentrations. The aims of the current work were to develop and validate a liquid chromatography/tandem mass spectrometry method for the simultaneous determination of 3 direct oral anticoagulants (dabigatran, rivaroxaban, and apixaban) in human plasma that is suitable for pharmacokinetic studies and routine therapeutic drug monitoring in busy hospital laboratories.. This method included a hydrolysis step to account for the active acylglucuronide metabolites of dabigatran that demonstrate an equivalent anticoagulant effect as dabigatran. After hydrolysis, a simple one-step protein precipitation was used for sample preparation. Total dabigatran (the sum of free dabigatran and the contribution from dabigatran acylglucuronides), rivaroxaban, and apixaban, and their corresponding isotopically labeled internal standards were resolved on a C18(2) column. All compounds were detected using electrospray ionization liquid chromatography/tandem mass spectrometry in the positive mode.. For all 3 anticoagulants, standard curves were linear over the concentration range of 1.0-1000 mcg/L (r > 0.99), bias was < ±10%, and intraday and interday coefficients of variation (imprecision) were <10%. The limit of quantification was 1.0 mcg/L. For all 3 anticoagulants and corresponding isotopically labeled internal standards, the absolute recoveries were similar and consistent, with mean values of 93%-102%. No significant matrix effects were observed.. This method is simple, rapid, robust, and reliable and can be used to analyze the plasma concentrations of the drugs in patients on dabigatran or rivaroxaban therapy.

Topics: Anticoagulants; Chromatography, Liquid; Dabigatran; Drug Monitoring; Humans; Pyrazoles; Pyridones; Reproducibility of Results; Rivaroxaban; Tandem Mass Spectrometry

Venous thromboembolism is a common complication among cancer patients with an estimated risk of 20%. American Society of Clinical Oncology guidelines recommend direct oral anticoagulants for long-term anticoagulation but caution the use of direct oral anticoagulants because of drug-drug interactions with antineoplastic therapies. The clinical impact of these drug-drug interactions is yet to be studied in clinical trials. This study aims to evaluate the effect of the drug-drug interactions on venous thromboembolism recurrence and bleeding.. This is a retrospective cohort study that included cancer patients with venous thromboembolism receiving apixaban or rivaroxaban with antineoplastic therapy. The impact of the drug-drug interaction was determined by its effect on the rates of venous thromboembolism recurrence and bleeding in patients with a drug-drug interaction compared to patients with no drug-drug interaction.. The primary composite endpoint of venous thromboembolism recurrence and bleeding events occurred in 65% versus 62% of patients in drug-drug interaction and non-drug-drug interaction groups accordingly. There was a higher rate of venous thromboembolism recurrence and minor bleeding events with anti-mitotic microtubule inhibitors and a higher rate of minor bleeding events with hormonal therapy and alkylating agents. Among the drug-drug interaction group, there were no major bleeding events reported with mild drug-drug interactions when compared to moderate-to-severe drug-drug interactions. There was no difference in time to venous thromboembolism recurrence between rivaroxaban and apixaban.. Due to small sample size, our study results could not confirm a higher risk of bleeding or venous thromboembolism recurrence with the drug-drug interactions. Further prospective study is warranted, but clinicians should be aware of these drug-drug interactions and identify them using available literature.

Topics: Aged; Anticoagulants; Drug Interactions; Female; Hemorrhage; Humans; Male; Middle Aged; Neoplasms; Pyrazoles; Pyridones; Recurrence; Retrospective Studies; Rivaroxaban; Venous Thromboembolism

The aim of the study was to perform analytical verification and comparison of chromogenic assays for determination of dabigatran, rivaroxaban and apixaban concentration on BCSXP and STA Compact Max analysers.. Precision, linearity, measurement uncertainty estimation and determination of limit of blank, limit of determination and limit of quantification were calculated. Analytical performance specifications were set according to manufacturer specifications and literature data on between laboratory variability. Comparison of the methods was done using Bland-Altman and Passing-Bablok regression analysis.. Obtained results have shown acceptable precision on STA Compact Max only for dabigatran (CV = 3.5%) at lower concentration level comparing to manufacturer declaration (CV = 3.6%). On BCSXP, the highest coefficient of variation has been shown for apixaban (6.1%) at lower concentration level. Within laboratory precision was not met on STA Compact Max for all assays. Bland-Altman analysis has shown statistically significant bias for dabigatran (23.2%, 95%CI 11.2 - 35.3; P < 0.001) and apixaban (8.4%, 95%CI 1.2 - 15.6; P = 0.023). Passing-Bablok regression analysis has shown systematic and proportional deviation between methods for rivaroxaban (y = 6.52 (2.94 to 11.83) + 0.84 (0.80 to 0.89) x.. Chromogenic assays for dabigatran, rivaroxaban and apixaban on BCSXP and STA Compact Max analysers are shown as methods with satisfactory long-term analytical performance specifications for determination of direct oral anticoagulants in clinical laboratories. However, we cannot recommend interchangeable use because of the significant bias between assays.

Topics: Anticoagulants; Blood Coagulation Tests; Dabigatran; Humans; Pyrazoles; Pyridones; Rivaroxaban

With safety concerns about increasing bleeding, off-label underdosing of non-vitamin K antagonist anticoagulants (NOACs) is common in East Asian patients with atrial fibrillation (AF). We tried to investigate the pattern of NOAC underdosing and associated clinical outcomes in patients with AF who are indicated for standard dosing. Using the Korean National Health Insurance Service database, we evaluated 16,568 patients with a new prescription of NOAC who are indicated for standard NOAC dosing and compared 4,536 patients with warfarin with respect to thromboembolic events (ischemic stroke or systemic embolization), all-cause mortality and major bleeding. Of the 16,568 patients indicated for standard NOAC dosing, 8,549 (51.9%) received off-label underdosing (50.6% rivaroxaban, 53.0% apixaban). During a median follow up of 15.0 months, as compared with warfarin, underdosing of rivaroxaban was associated with lower risks of major thromboembolic events (hazard ratio [HR]: 0.53; 95% confidence interval [CI]: 0.41 to 0.69) and all-cause mortality (HR 0.57, 95% CI: 0.41 to 0.82), and a similar risk of major bleeding (HR 1.10, 95% CI: 0.82 to 1.46). However, underdosing of apixaban was associated with similar risks of major thromboembolic events (HR: 0.90; 95% CI: 0.70 to 1.16), all-cause mortality (HR 0.94, 95 CI: 0.71 to 1.24) and major bleeding (HR 0.84, 95% CI: 0.61 to 1.17). In conclusion, in this Korean population with AF who are indicated for standard NOAC dosing, off-label underdosing is common and its clinical benefit over warfarin was inconsistent according to types of NOAC. Notably, apixaban underdosing provides no benefit in effectiveness compared with warfarin.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Cohort Studies; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Off-Label Use; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thromboembolism; Warfarin

Topics: Administration, Oral; Atrial Fibrillation; Embolism; Factor Xa Inhibitors; Humans; Pyrazoles; Pyridones; Rivaroxaban; Stroke

Apixaban and rivaroxaban are the most commonly prescribed direct oral anticoagulants for adults with atrial fibrillation, but head-to-head data comparing their safety and effectiveness are lacking.. To compare the safety and effectiveness of apixaban versus rivaroxaban for patients with nonvalvular atrial fibrillation.. New-user, active-comparator, retrospective cohort study.. A U.S. nationwide commercial health care claims database from 28 December 2012 to 1 January 2019.. Adults newly prescribed apixaban (n = 59 172) or rivaroxaban (n = 40 706).. The primary effectiveness outcome was a composite of ischemic stroke or systemic embolism. The primary safety outcome was a composite of intracranial hemorrhage or gastrointestinal bleeding.. 39 351 patients newly prescribed apixaban were propensity score matched to 39 351 patients newly prescribed rivaroxaban. Mean age was 69 years, 40% of patients were women, and mean follow-up was 288 days for new apixaban users and 291 days for new rivaroxaban users. The incidence rate of ischemic stroke or systemic embolism was 6.6 per 1000 person-years for adults prescribed apixaban compared with 8.0 per 1000 person-years for those prescribed rivaroxaban (hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.98]; rate difference, 1.4 fewer events per 1000 person-years [CI, 0.0 to 2.7]). Adults prescribed apixaban also had a lower rate of gastrointestinal bleeding or intracranial hemorrhage (12.9 per 1000 person-years) compared with those prescribed rivaroxaban (21.9 per 1000 person-years), corresponding to an HR of 0.58 (CI, 0.52 to 0.66) and a rate difference of 9.0 fewer events per 1000 person-years (CI, 6.9 to 11.1).. Unmeasured confounding, incomplete laboratory data.. In routine care, adults with atrial fibrillation prescribed apixaban had a lower rate of both ischemic stroke or systemic embolism and bleeding compared with those prescribed rivaroxaban.. Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital.

Topics: Administration, Oral; Aged; Atrial Fibrillation; Embolism; Factor Xa Inhibitors; Female; Humans; Incidence; Male; Propensity Score; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke

Factor Xa (FXa) inhibitors are recommended for use in fixed doses without laboratory monitoring. However, prior studies reported the importance of establishing biomarkers representing anticoagulation intensity related to bleeding or thrombotic events. To test the hypothesis that prothrombin activation fragment 1 and 2 (F1 + 2), a non-specific marker of thrombin generation, could be altered during FXa inhibitor treatment in patients with atrial fibrillation. We conducted the study in two different clinical settings. First, the interrelations among biomarkers representing coagulation/fibrinolysis were investigated in 80 patients in an outpatient clinic. Second, these biomarkers were evaluated in 75 patients who underwent radiofrequency catheter ablation. Plasma concentration of FXa inhibitors was evaluated using an anti-FXa chromogenic assay (C-Xa). In the outpatient study, only F1 + 2 exhibited a significant and negative association with C-Xa (rS =  - 0.315, p = 0.026), and 37% of the variance could be explained by C-Xa levels. F1 + 2 levels above the reference range (> 229 pmol/L) could be considered as a cut-off to identify poor patient compliance or under-dosing. In the peri-ablation study, increased F1 + 2 levels were associated with decline of C-Xa levels after periprocedural discontinuation of FXa inhibitors, which was greater in the rivaroxaban group than in the apixaban group. F1 + 2 showed modest and inverse association with plasma concentration of rivaroxaban and apixaban in patients with atrial fibrillation. Larger study to test the hypothesis that continued thrombin generation despite anticoagulation is associated with a heightened risk of clinical events is required.

Topics: Aged; Aged, 80 and over; Atrial Fibrillation; Biomarkers; Catheter Ablation; Drug Monitoring; Factor Xa Inhibitors; Female; Humans; Male; Peptide Fragments; Prothrombin; Pyrazoles; Pyridones; Rivaroxaban; Time Factors; Treatment Outcome

Since 2012 four direct oral anticoagulants (DOAC) have been approved by the US Food and Drug Administration (FDA) for treatment of acute venous thromboembolism (VTE). Clinical trials comparing DOACs to warfarin included more than 13,500 patients. However, included patients were all age 39 years or older. We sought to describe real-world use of DOACs among young adults with acute VTE. Multi-center retrospective case series of young adult patients (age 18-40 years) at two large academic medical centers who initiated any DOAC for VTE therapy in 2015 or 2016. Thrombotic and bleeding events as well as off-label drug use were described using summary statistics. Fifty-seven patients were identified (63.2% female). One of the 57 patients (1.8%) had a thromboembolic event. Seven of the 57 patients (12.3%) experienced a bleeding event, one categorized as a major bleed and six being categorized as clinically relevant non-major bleeding. One of the ten (10%) patients receiving apixaban was not initiated on the FDA-recommended 10 mg twice daily for the first 7 days. Seven of the 47 (14.9%) patients receiving rivaroxaban were not initiated on the FDA-recommended 15 mg twice daily dosing for the first 21 days. Bleeding occurred in approximately 14% of young adult patients treated with DOAC therapy. However, only one patient had their DOAC discontinued due to a major bleeding event. Recurrence of DVT while on DOAC therapy was rare.

Topics: Acute Disease; Adult; Age Factors; Dose-Response Relationship, Drug; Electronic Health Records; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Off-Label Use; Practice Guidelines as Topic; Pyrazoles; Pyridones; Recurrence; Retrospective Studies; Rivaroxaban; United States; Venous Thromboembolism

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

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

Clinical studies are needed to clarify the use of direct oral anticoagulants (DOACs) in breastfeeding women. To support emerging clinical studies on investigating DOAC's transfer into breast milk, an ultra-high-performance liquid chromatography/tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for quantifying three DOACs - apixaban, edoxaban and rivaroxaban in human plasma and breast milk. Protein precipitation with methanol was performed for sample preparation. Chromatographic analysis was performed using a C18 column. The MS detection was performed in MRM mode. The method was validated in accordance with the European Guideline (EMA). The calibration range was 5-500 ng/mL in plasma and 5-250 ng/mL in breast milk. The within-batch and between-batch variability remained <9%. Recoveries ranged from 106.13% to 109.05% in plasma and from 93.40% to 107.91% in breast milk. The lot-to-lot matrix variability was within ±15% among a range of samples originating from many different subjects. All analytes were stable when stored for 24 h at room temperature, 7 days at 2-8 °C, and at least 5 weeks at -20 °C in both plasma and breast milk. The developed method fulfilled the EMA bioanalytical method validation guideline and was shown to be simple, fast, accurate and will now be used in a clinical trial evaluating the transfer of apixaban and rivaroxaban into human breast milk.

Topics: Administration, Oral; Anticoagulants; Breast Feeding; Chromatography, High Pressure Liquid; Female; Humans; Lactation; Limit of Detection; Milk, Human; Molecular Structure; Pyrazoles; Pyridines; Pyridones; Reproducibility of Results; Rivaroxaban; Tandem Mass Spectrometry; Thiazoles

Since the approval of the oral factor Xa inhibitors, there have been concerns regarding the ability to neutralize their anticoagulant effects after intracranial hemorrhage (ICH). Multiple guidelines suggest using prothrombin complex concentrates (PCCs) in these patients on the basis of research that includes a limited number of patients with ICH. Given this, we aimed to evaluate the safety and efficacy of PCCs for factor Xa inhibitor-related ICH in a large, multicenter cohort of patients.. This was a multicenter, retrospective, observational cohort study of patients with apixaban- or rivaroxaban-related ICH who received PCCs between January 1, 2015, and March 1, 2019. The study had 2 primary analysis groups: safety and hemostatic efficacy. The safety analysis evaluated all patients meeting inclusion criteria for the occurrence of a thrombotic event, which were censored at hospital discharge or 30 days after PCC administration. Patients with intracerebral, subarachnoid, or subdural hemorrhages who had at least 1 follow-up image within 24 hours of PCC administration were assessed for hemostatic efficacy. The primary efficacy outcome was the percentage of patients with excellent or good hemostasis on the basis of the modified Sarode criteria. Secondary outcomes included an evaluation of in-hospital mortality, length of stay, infusion-related reactions, and thrombotic event occurrence during multiple predefined periods.. A total of 663 patients were included and assessed for safety outcomes. Of these, 433 patients met criteria for hemostatic efficacy evaluation. We observed excellent or good hemostasis in 354 patients (81.8% [95% CI, 77.9-85.2]). Twenty-five (3.8%) patients had a total of 26 thrombotic events, of which 22 occurred in the first 14 days after PCC administration. One patient had documentation of an infusion-related reaction. For the full cohort of patients, in-hospital mortality was 19.0%, and the median intensive care unit and hospital lengths of stay were 2.0 and 6.0 days, respectively.. Administration of PCCs after apixaban- and rivaroxaban-related ICH provided a high rate of excellent or good hemostasis (81.8%) coupled with a 3.8% thrombosis rate. Randomized, controlled trials evaluating the clinical efficacy of PCCs in patients with factor Xa inhibitor-related ICH are needed.

Topics: Aged; Blood Coagulation Factors; Factor Xa Inhibitors; Female; Hematoma, Subdural; Hemostasis; Hemostatics; Hospital Mortality; Humans; Intracranial Thrombosis; Length of Stay; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Risk Factors; Rivaroxaban; Subarachnoid Hemorrhage; Time Factors; Treatment Outcome; United States

Randomized controlled trials leading to the approval of apixaban and rivaroxaban for venous thromboembolism (VTE) did not include patients with upper extremity deep vein thrombosis (UE-DVT). We sought to evaluate the safety and effectiveness of rivaroxaban and apixaban for the treatment of acute UE-DVT. Consecutive patients with VTE enrolled into the Mayo Clinic VTE Registry, between March 1, 2013 and December 31, 2019, were followed prospectively. Clinical, demographic and imaging data were collected at the time of study recruitment. Patients with a diagnosis of acute UE-DVT who received rivaroxaban, apixaban, LMWH or warfarin were included. Recurrent VTE, major bleeding, clinical-relevant non-major bleeding (CRNMB), and death were assessed at 3-month intervals. During the study period, 210 patients with acute UE-DVT were included; 63 were treated with apixaban, 39 with rivaroxaban, and 108 with LWMH and/or warfarin. Overall 51% had catheter-associated UE-DVT, 60% had a diagnosis of malignancy, and 14% had concurrent pulmonary embolism. Malignancy was more common in patients treated with LMWH/warfarin (67% vs 52%, P = .03). At 3 months of follow up, one (0.9%) recurrent VTE occurred in a patient treated with LMWH/warfarin and one (1.0%) patient treated with apixaban or rivaroxaban (P = .97). Major bleeding occurred in three patients treated with LMWH/warfarin, and in none of those treated with apixaban or rivaroxaban (P = .09). Clinical-relevant non-major bleeding occurred in one patient (0.9%) treated with LWMH/warfarin and two patients (2.0%) treated with apixaban or rivaroxaban (P = .53). Treatment of UE-DVT with apixaban or rivaroxaban appears to be as safe and effective as LMWH/warfarin.

Topics: Aged; Female; Follow-Up Studies; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Registries; Rivaroxaban; Upper Extremity; Venous Thrombosis; Warfarin

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

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

Topics: Atrial Fibrillation; Humans; Pyrazoles; Pyridones; Rivaroxaban; Stroke

Before approval of andexanet alfa, off-label treatment with 4-factor prothrombin complex concentrate (4F-PCC) was often utilized for the management of life-threatening hemorrhages associated with oral factor Xa inhibitors. We evaluated the operational processes and outcomes of patients with oral factor Xa inhibitor-associated intracranial hemorrhages (ICH) treated with andexanet alfa or 4F-PCC.. We performed a retrospective, single-center case series of rivaroxaban or apixaban-associated ICH between 2016-2019 treated with andexanet alfa or 4F-PCC. Good or excellent hemostatic effectiveness, good functional outcome (Glasgow Outcome Score [GOS]> 3) at hospital discharge, and incidence of thrombosis within 30 days were reported.. Eighteen patients were included in the andexanet alfa cohort and 11 in the 4F-PCC cohort. Excellent or good hemostasis occurred in 88.9% of andexanet alfa-treated patients and 60% of 4F-PCC-treated patients. Good functional outcome on discharge occurred in 55.6% of andexanet alfa-treated patients and 9.1% of 4F-PCC-treated patients. Thrombotic complications occurred in 16.7% of andexanet alfa-treated patients and 9.1% of 4F-PCC-treated patients. Median order-to-administration time was 1.1 hours [0.8-1.4] versus 0.5 hours [0.1-0.8] in the andexanet alfa and 4F-PCC group, respectively. The median cost of therapy was $29970/patient versus $6925/patient in the andexanet alfa and 4F-PCC group, respectively.. We observed higher rates of occurrence of good or excellent hemostasis and GOS > 3 on hospital discharge and increased incidence of thrombosis in patients who received andexanet alfa compared to 4F-PCC for oral factor Xa inhibitor reversal. However, patients receiving 4F-PCC had lower pre-reversal Glasgow Coma Scale (GCS)score and larger pre-reversal ICH volume.

Topics: Blood Coagulation Factors; Factor Xa; Factor Xa Inhibitors; Humans; Intracranial Hemorrhages; Pyrazoles; Pyridones; Recombinant Proteins; Retrospective Studies; Rivaroxaban

Approximately 1-2% of patients with non-valvular atrial fibrillation have an acute ischemic stroke (AIS) while on direct oral anticoagulant (DOAC) treatment every year. However, current evidence on stroke subtypes, pathophysiology and factors leading to the failure of DOAC preventive therapy in a "real world" setting is still scanty. This study aimed at investigating whether there is any relationship between DOAC plasma levels and the stroke occurrence, on the basis of the phenotypic classification and pathophysiology of the stroke, in a cohort of DOAC-treated patients admitted to our hospital for AIS over 1-year period. A total of 28 patients had DOAC plasma levels determined in emergency and were included in the study, nine patients receiving dabigatran, 11 rivaroxaban and 8 apixaban. The DOAC levels were low in 8/28 patients (28.6% of the sample), intermediate in 4 (14.3%) and high in 16 (57.1%). The most prevalent stroke subtype was the small vessel disease, according to the A-S-C-O phenotypic classification, in 53.6% of our sample. The most common clinical presentation was "minor stroke" in 71.4% of the cases. There was a significantly higher proportion of patients with high DOAC levels in the small vessel group, compared to the cardioembolic group without other phenotypes. The question arises as to the most suitable clinical management of AIS in these patients on DOACs. In the current absence of clear evidence, taking into account the DOAC levels (low/intermediate/high) and the underlying stroke pathophysiology, we present a flowchart of our proposed clinical management of ischemic stroke in patients while on DOAC.

Topics: Aged; Aged, 80 and over; Atrial Fibrillation; Dabigatran; Disease Management; Drug Monitoring; Factor Xa Inhibitors; Female; Humans; Ischemic Stroke; Italy; Male; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban

Factor-Xa inhibitors (FXaIs) are widely used for the treatment of non-valvular atrial fibrillation (NVAF). Although we have previously reported the distribution of the anti-factor Xa activity (AXA) values of three different FXaIs in NVAF patients, the differences in the distribution of AXA values among the different FXaIs in patients with renal impairment (RI) have not been fully elucidated.. Trough and peak AXA values were measured in 94 patients taking rivaroxaban, 124 patients taking apixaban, and 66 patients taking edoxaban. Of them, we identified 26 patients with moderate RI [creatinine clearance (CrCl) 30-49 mL/min] and 17 patients with severe RI (CrCl 15-29 mL/min) in the rivaroxaban cohort, 37 patients with moderate RI and 17 patients with severe RI in the apixaban cohort, and 21 patients with moderate RI and 9 patients with severe RI in the edoxaban cohort. AXA values were measured using chromogenic AXA assays. Both trough and peak AXA values were compared between patients with moderate RI and those with severe RI in each cohort, and differences in the peak-to-trough ratio among the different drugs were assessed.. In the rivaroxaban cohort, the peak AXA value was significantly higher in patients with severe RI than in those with moderate RI. In the apixaban cohort, neither the trough nor peak AXA values significantly differed between patients with moderate RI and those with severe RI. In the edoxaban cohort, the trough AXA value was significantly higher in patients with severe RI than in those with moderate RI, and peak AXA tended to be higher in patients with severe RI. The peak-to-trough ratio of AXA values was significantly lower in patients taking apixaban than in those taking rivaroxaban and edoxaban.. Among Japanese NVAF patients with RI, the peak or trough AXA values were higher in patients with severe RI than in those with moderate RI when taking rivaroxaban and edoxaban, whereas both the peak and trough AXA values were similar between patients with severe RI and those with moderate RI when taking apixaban. The peak-to-trough ratio of AXA values was the lowest in patients taking apixaban.

Topics: Aged; Aged, 80 and over; Atrial Fibrillation; Cohort Studies; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Pyrazoles; Pyridines; Pyridones; Renal Insufficiency; Rivaroxaban; Thiazoles

Topics: Access to Information; Cause of Death; Disclosure; Factor Xa Inhibitors; Fraud; Humans; Multicenter Studies as Topic; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Research Report; Rivaroxaban; Scientific Misconduct; United States; United States Food and Drug Administration

The safety and efficacy of nonvitamin K antagonist oral anticoagulants (NOACs) for the treatment of venous thromboembolism (VTE) have been established in randomized controlled trials, but limited data are available on their use in clinical practice across geographical regions.. In the international RE-COVERY DVT/PE observational study (enrollment January 2016 to May 2017), we sought to characterize the patient population and describe the prescribed anticoagulant. Patient characteristics and anticoagulants administered after objective diagnosis of VTE were recorded at the baseline visit and again at hospital discharge or at 14 days after the diagnosis, whichever was later.. A total of 6095 patients were included, 50.2% were male, and the mean age was 61.5 years. The most common comorbidities were hypertension (35%), diabetes mellitus (11%), cancer (11%), prior VTE(11%), and trauma/surgery (7%). Overall, 77% of patients received oral anticoagulants, with 54% on NOACs and 23% on vitamin K antagonists (VKAs); 20% received parenteral anticoagulation only. NOACs comprised about 60% of anticoagulant treatment in Europe and Asia but substantially less in Latin America (29%) and the Middle East (21%). For NOAC therapies, the distribution (as a percentage of the total cohort) was rivaroxaban 25.6%, dabigatran 15.5%, apixaban 11.3%, and edoxaban 1.7%. Treatment with NOACs was less frequent in patients who had cancer, chronic renal disease, heart failure, or stroke.. These findings enhance our understanding of baseline characteristics and the initial management of patients with VTE in routine practice.

Topics: Administration, Oral; Adult; Age Distribution; Aged; Anticoagulants; Asia; Comorbidity; Cross-Sectional Studies; Dabigatran; Diabetes Mellitus; Europe; Factor Xa Inhibitors; Female; Fondaparinux; Heparin; Humans; Hypertension; Latin America; Male; Middle Aged; Middle East; Neoplasms; Postoperative Complications; Practice Patterns, Physicians'; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Venous Thromboembolism; Venous Thrombosis; Wounds and Injuries

Evidence for the efficacy of direct oral anticoagulants (DOACs) to prevent cardiovascular (CV) events and mortality in older individuals with a low estimated glomerular filtration rate (eGFR) is lacking. We sought to characterize the association of oral anticoagulant use with CV morbidity in elderly patients with or without reductions in eGFRs, comparing DOACs with vitamin K antagonists (VKAs).. Population-based retrospective cohort study.. All individuals 66 years or older with an initial prescription for oral anticoagulants dispensed in Ontario, Canada, from 2009 to 2016.. DOACs (apixaban, dabigatran, and rivaroxaban) compared with VKAs by eGFR group (≥60, 30-59, and<30mL/min/1.73m. The primary outcome was a composite of a CV event (myocardial infarction, revascularization, or ischemic stroke) or mortality. Secondary outcomes were CV events alone, mortality, and hemorrhage requiring hospitalization.. High-dimensional propensity score matching of DOAC to VKA users and Cox proportional hazards regression.. 27,552 new DOAC users were matched to 27,552 new VKA users (median age, 78 years; 49% women). There was significantly lower risk for CV events or mortality among DOAC users compared with VKA users (event rates of 79.78 vs 99.77 per 1,000 person-years, respectively; HR, 0.82 [95% CI, 0.75-0.90]) and lower risk for hemorrhage (event rates of 10.35 vs 16.77 per 1,000 person-years, respectively; HR, 0.73 [95% CI, 0.58-0.91]). There was an interaction between eGFR and the association of anticoagulant class with the primary composite outcome (P<0.02): HRs of 1.01 [95% CI, 0.92-1.12], 0.83 [95% CI, 0.75-0.93], and 0.75 [95% CI, 0.51-1.10] for eGFRs of≥60, 30 to 59, and<30mL/min/1.73m. Retrospective observational study design limits causal inference; dosages of DOACs and international normalized ratio values were not available; low event rates in some subgroups limited statistical power.. DOACs compared with VKAs were associated with lower risk for the composite of CV events or mortality, an association for which the strength was most apparent among those with reduced eGFRs. The therapeutic implications of these findings await further study.

Topics: Aged; Aged, 80 and over; Antithrombins; Brain Ischemia; Cause of Death; Comorbidity; Dabigatran; Female; Glomerular Filtration Rate; Hemorrhage; Humans; Male; Mortality; Myocardial Infarction; Myocardial Revascularization; Ontario; Procedures and Techniques Utilization; Propensity Score; Proportional Hazards Models; Pyrazoles; Pyridones; Renal Insufficiency, Chronic; Retrospective Studies; Rivaroxaban; Thrombophilia; Vitamin K

Warfarin is standard anticoagulation therapy for patients with a continuous-flow left ventricular assist device (CF-LVAD). However, warfarin requires regular monitoring and dosage adjustments and fails for many patients, causing thromboembolic and bleeding events. Factor Xa inhibitors have been shown to be noninferior to warfarin in preventing strokes and are associated with less intracranial hemorrhage in patients with atrial fibrillation. We evaluated treatment safety and effectiveness in CF-LVAD patients who switched from warfarin to a factor Xa inhibitor (apixaban or rivaroxaban) after warfarin failure.. This was a retrospective, single-center study of patients treated between 2008 and 2018. We assessed the occurrence of stroke, non-central nervous system (CNS) embolism, pump thrombosis, and major gastrointestinal bleeding and intracranial hemorrhage during therapy.. Factor Xa inhibitors may be viable treatment options for CF-LVAD patients for whom warfarin therapy has failed. Large prospective studies are necessary to confirm these results.

Topics: Factor Xa Inhibitors; Female; Heart Failure; Heart-Assist Devices; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Thromboembolism; Treatment Outcome; Warfarin

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

It remains unknown whether the comparative effectiveness of direct oral anticoagulants (DOACs) and warfarin differs between atrial fibrillation patients with and without a history of stroke or transient ischemic attack (TIA). Using 2012 to 2014 Medicare claims data, we identified patients newly diagnosed with AF in 2013 to 2014 who initiated apixaban, dabigatran, rivaroxaban, or warfarin. We categorized patients based on a history of stroke or TIA. We constructed Cox proportional hazard models that included indicator variables for treatment groups, a history of stroke or TIA, and the interaction between them, and controlled for demographics and clinical characteristics. DOACs were generally more effective than warfarin in stroke prevention; however, there were important differences between subgroups defined by a history of ischemic stroke. In particular, the superiority of dabigatran compared with warfarin in ischemic stroke prevention was more pronounced in patients with a history of stroke or TIA (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.48 to 0.85) than in patients with no history of stroke or TIA (HR 0.94; 95% CI 0.75 to 1.16; p value for interaction = 0.034). There was no difference in the risk of stroke between apixaban, dabigatran, and rivaroxaban in patients with no history of stroke or TIA. However, in patients with a history of stroke or TIA, the risk of stroke was lower with dabigatran (HR 0.64; 95% CI 0.48 to 0.85) and rivaroxaban (HR 0.70; 95% CI 0.56 to 0.87), compared with apixaban (p value for both interactions <0.05). In conclusion, the comparative effectiveness of DOACs differs substantially between patients with and without a history of stroke or TIA; specifically, apixaban is less effective in patients with a history of stroke or TIA.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Cohort Studies; Dabigatran; Female; Hemorrhage; Humans; Ischemic Attack, Transient; Male; Medicare; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; United States; Warfarin

Hospitalized patients with acute medical illnesses are at risk for venous thromboembolism (VTE) during and after a hospital stay. Risk factors include physical immobilization and underlying pathophysiologic processes that activate the coagulation pathway and are still present after discharge. Strategies for optimal pharmacologic VTE thromboprophylaxis are evolving, and recommendations for VTE prophylaxis can be further refined to protect high-risk patients after hospital discharge. An early study of extended VTE prophylaxis with a parenteral agent in medically ill patients yielded inconclusive results with regard to efficacy and bleeding. In the Acute Medically Ill VTE Prevention with Extended Duration Betrixaban (APEX) trial, extended use of betrixaban halved symptomatic VTE, decreased hospital readmission, and reduced stroke and major adverse cardiovascular events compared with standard enoxaparin prophylaxis. Based on findings from APEX, the Food and Drug Administration approved betrixaban in 2017 for extended VTE prophylaxis in acute medically ill patients. In the Reducing Post-Discharge Venous Thrombo-Embolism Risk (MARINER) study, extended use of rivaroxaban halved symptomatic VTE in high-risk medical patients compared with placebo. In 2019, rivaroxaban was approved for extended thromboprophylaxis in high-risk medical patients, thus making available a new strategy for in-hospital and post-discharge VTE prevention. To address the critical unmet need for VTE prophylaxis in medically ill patients at the time of hospital discharge, the North American Thrombosis Forum (NATF) is launching the Anticoagulation Action Initiative, a comprehensive consensus document that provides practical guidance and straightforward, patient-centered recommendations for VTE prevention during hospitalization and after discharge.

Topics: Adult; Aged; Anticoagulants; Benzamides; Hospitalization; Humans; Medication Adherence; Middle Aged; Patient Discharge; Practice Guidelines as Topic; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Risk Factors; Rivaroxaban; Venous Thromboembolism

It is unclear whether anticoagulant type is associated with the risk for osteoporotic fracture, a deleterious complication of anticoagulants among patients with atrial fibrillation (AF).. To compare the risk for osteoporotic fracture between anticoagulants.. Population-based cohort study.. Territory-wide electronic health record database of the Hong Kong Hospital Authority.. Patients newly diagnosed with AF between 2010 and 2017 who received a new prescription for warfarin or a direct oral anticoagulant (DOAC) (apixaban, dabigatran, or rivaroxaban). Follow-up ended on 31 December 2018.. Osteoporotic hip and vertebral fractures in anticoagulant users were compared using propensity score-weighted cumulative incidence differences (CIDs).. There were 23 515 patients identified (3241 apixaban users, 6867 dabigatran users, 3866 rivaroxaban users, and 9541 warfarin users). Overall mean age was 74.4 years (SD, 10.8), ranging from 73.1 years (warfarin) to 77.9 years (apixaban). Over a median follow-up of 423 days, 401 fractures were identified (crude event number [weighted rate per 100 patient-years]: apixaban, 53 [0.82]; dabigatran, 95 [0.76]; rivaroxaban, 57 [0.67]; and warfarin, 196 [1.11]). After 24-month follow-up, DOAC use was associated with a lower risk for fracture than warfarin use (apixaban CID, -0.88% [95% CI, -1.66% to -0.21%]; dabigatran CID, -0.81% [CI, -1.34% to -0.23%]; and rivaroxaban CID, -1.13% [CI, -1.67% to -0.53%]). No differences were seen in all head-to-head comparisons between DOACs at 24 months (apixaban vs. dabigatran CID, -0.06% [CI, -0.69% to 0.49%]; rivaroxaban vs. dabigatran CID, -0.32% [CI, -0.84% to 0.18%]; and rivaroxaban vs. apixaban CID, -0.25% [CI, -0.86% to 0.40%]).. Residual confounding is possible.. Among patients with AF, DOAC use may result in a lower risk for osteoporotic fracture compared with warfarin use. Fracture risk does not seem to be altered by the choice of DOAC. These findings may help inform the benefit-risk assessment when choosing between anticoagulants.. The University of Hong Kong and University College London Strategic Partnership Fund.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Cohort Studies; Dabigatran; Female; Follow-Up Studies; Hip Fractures; Hong Kong; Humans; Male; Osteoporotic Fractures; Pyrazoles; Pyridones; Rivaroxaban; Spinal Fractures; Stroke; Warfarin

Topics: 4-Hydroxycoumarins; Adult; Aftercare; Anticoagulants; Antiphospholipid Syndrome; England; Factor Xa Inhibitors; Fibrin Fibrinogen Degradation Products; Heparin, Low-Molecular-Weight; Humans; Incidence; Indenes; International Normalized Ratio; Neoplasms; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; State Medicine; Systematic Reviews as Topic; Thrombophilia; Vena Cava Filters; Venous Thromboembolism; Vitamin K

Oral factor Xa inhibitors (OFXais) may interfere with the heparin antifactor Xa (antiXa) assay. The best method to measure heparin activity during the transition from an OFXai to intravenous (IV) unfractionated heparin (UFH) remains unknown. This study aimed to assess the safety and effectiveness of transitioning from an OFXai to UFH.. A retrospective analysis was conducted of patients with supratherapeutic antiXa levels on UFH who received either apixaban or rivaroxaban within 72 hours before UFH initiation at NYU Langone Health. The primary objective was to identify the incidence of interference on the heparin antiXa assay due to OFXai exposure in the previous 72 hours. The secondary outcomes included the indication for transition to UFH and the rate of thromboembolic and bleeding events.. A total of 93 patients with supratherapeutic antiXa activity levels with prior OFXai use were reviewed. Moderate renal impairment, defined as creatinine clearance less than 49 mL/min, was present in 67 (72%) patients. The primary indication for transition from OFXai to UFH was in anticipation for a procedure, and it occurred in 37 (40%) patients. There were 3 major bleeding events and 3 clinically relevant nonmajor bleeding events. No thromboembolic events occurred.. This study assessed the prevalence of supratherapeutic antiXa levels and clinical outcomes during the transition from OFXais to UFH. Health care systems should develop guidelines to assist clinicians in monitoring antiXa activity in patients undergoing a transition from an OFXai to UFH. It is also important to assess the patient's underlying thromboembolic and bleeding risks.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation Tests; Drug Monitoring; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Hemorrhage; Heparin; Humans; Male; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Thromboembolism

Topics: Administration, Oral; Alopecia; Anticoagulants; Dabigatran; Data Mining; Databases, Factual; Humans; Minoxidil; Pharmacovigilance; Platelet-Rich Plasma; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles

The speed of adoption of new drugs and frequencies of substitutions leads to changes in health care expenditures as well as patient outcomes. In this study, we aim to understand the speed of adoption of new drugs and their prescription volume in health care institutions and evaluate the impact of policy options to manage pharmaceutical expenditure.. We conducted a retrospective cohort study of health care institutions prescribing NOACs, including Apixaban, Dabigatran, and Rivaroxaban, to address the speed of adoption and their substitution from October 1, 2010, through December 31, 2015, using the National Health Insurance Service-National Sample Cohort. Two threshold time points, including the extension of reimbursement with the need for the letter of opinion and the withdrawal of the letter of opinion, were noted in this study. Then, we applied a survival analysis to elucidate factors that affected the speed of adoption of NOACs, and interrupted time series analysis to estimate the effect of amendments in reimbursement coverage in prescription volume.. Among 934 health care institutions in a study population, 334 institutions (36%) had prescribed NOACs at least one time during the study period, indicating that health care institutions were conservative in adopting new drugs. However, the speed of adoption was related to the characteristics of health care institution. We also found that prescriptions of NOACs before the withdrawal of the need for the letter of opinion were marginal, and the prescription volume of NOACs was significantly increased after the withdrawal of a letter of opinion.. Health care institutions were conservative in adopting new drugs, and the speed of adoption is not closely related to an increased prescription volume in the short run. Thus, policies that are centered on managing pharmaceutical expenditure should be devised with considering the impact of introducing new drugs in the long run. A letter of opinion, which was devised to manage prescriptions of NOACs, was effective in managing pharmaceutical expenditures in health care institutions, particularly for tertiary institutions. Conversely, the withdrawal of the need for the letter of opinion should be implemented with caution.

Topics: Adult; Aged; Anticoagulants; Atrial Fibrillation; Cohort Studies; Dabigatran; Drug Prescriptions; Health Expenditures; Humans; Interrupted Time Series Analysis; Middle Aged; National Health Programs; Practice Patterns, Physicians'; Primary Health Care; Pyrazoles; Pyridones; Republic of Korea; Retrospective Studies; Rivaroxaban

The risk of liver injury in patients with atrial fibrillation (AF) using nonvitamin K antagonist oral anticoagulants (NOACs) has not been previously examined using liver function tests as the primary outcome in the real-world setting. This study assessed the association between NOACs (dabigatran, rivaroxaban, and apixaban) and warfarin and the risk of liver injury, as defined by laboratory tests.. Patients newly diagnosed with AF and prescribed NOACs or warfarin between 2010 and 2016, identified using the Hong Kong Clinical Database and Reporting System, were matched on age, sex, health status scores, comorbidities, and medications by propensity score on a 1:1 ratio. Risk of liver injury, defined as laboratory test values >3 times the upper limit of normal of alanine aminotransferase or aspartate aminotransferase and >2 times the upper limit of normal of total bilirubin, was compared between NOAC and warfarin users using Cox proportional hazards regression.. After propensity score matching, 13,698 patients were included, of which 141 (2.1%) NOAC users and 232 (3.4%) warfarin users developed liver injury. The hazard ratio (HR) for NOAC vs warfarin users was 0.71 (95% confidence interval: 0.58-0.89). When comparing individual NOACs, only dabigatran (hazard ratio: 0.63; 95% confidence interval: 0.48-0.82) was associated with a lower risk of liver injury.. Among patients with AF, NOACs as a group, and dabigatran alone were associated with a significantly lower risk of laboratory-based liver injury when compared with warfarin. However, liver injury occurs more frequently in real-world practice than in NOAC randomized controlled trials.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Chemical and Drug Induced Liver Injury; Cohort Studies; Dabigatran; Databases, Factual; Female; Humans; Male; Middle Aged; Propensity Score; Pyrazoles; Pyridones; Risk; Rivaroxaban; Warfarin

Topics: Drug Monitoring; Factor Xa Inhibitors; Female; Humans; Milk, Human; Postpartum Period; Pyrazoles; Pyridones; Rivaroxaban; Time Factors; Venous Thromboembolism

Warfarin is an anticoagulant medication proven effective in the initial treatment and secondary prevention of venous thromboembolism. Anti-Xa direct oral anticoagulants are alternatives to warfarin; however there is limited data assessing satisfaction after switching from warfarin to an anti-Xa direct oral anticoagulant in patients for treatment of venous thromboembolism.. To assess medication satisfaction in patients requiring anticoagulation for venous thromboembolism after conversion from warfarin to an anti-Xa direct oral anticoagulant.. A retrospective cohort study with prospective assessment of satisfaction and review of adverse events following anti-Xa direct oral anticoagulant replacement of warfarin for treatment of venous thromboembolism. Out of 165 patients who had switched from warfarin to rivaroxaban or apixaban from an outpatient haematology practice, 126 patients consented for a survey of patient's relative satisfaction of anti-Xa direct oral anticoagulant therapy compared with previous warfarin therapy using the Anti-Clot Burden and Benefits Treatment Scale and SWAN Score.. The mean Anti-Clot Burden and Benefits and SWAN Score was 93% (56/60) and 83% (24.8/30) respectively reflecting high satisfaction with anti-Xa direct oral anticoagulants. 120 patients stated preference for anti-Xa direct oral anticoagulants over warfarin. Leading perceptions driving this was the reduction in frequency of medical contact and fewer bleeding side effects. Thirteen patients (10.3%) experienced an adverse event after the anti-Xa direct oral anticoagulant switch (majority were non-major bleeding) but most remained on anti-Xa direct oral anticoagulant treatment after management options were implemented with continued high satisfaction scores.. Patient satisfaction with anti-Xa direct oral anticoagulant therapy for the treatment and prevention of venous thromboembolism after switching from warfarin in routine clinical practice appeared high. Improved patient convenience including reduced frequency of medical contact and fewer unpredictable side effects were perceived as significant advantages of anti-Xa direct oral anticoagulants compared to warfarin.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Cohort Studies; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Patient Satisfaction; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Surveys and Questionnaires; Time Factors; Venous Thromboembolism; Warfarin; Young Adult

Clarithromycin is a commonly prescribed antibiotic associated with higher levels of direct oral anticoagulants (DOACs) in the blood, with the potential to increase the risk of hemorrhage.. To assess the 30-day risk of a hospital admission with hemorrhage after coprescription of clarithromycin compared with azithromycin among older adults taking a DOAC.. This population-based, retrospective cohort study was conducted among adults of advanced age (mean [SD] age, 77.6 [7.2] years) who were newly coprescribed clarithromycin (n = 6592) vs azithromycin (n = 18 351) while taking a DOAC (dabigatran, apixaban, or rivaroxaban) in Ontario, Canada, from June 23, 2009, to December 31, 2016. Cox proportional hazards regression was used to examine the association between hemorrhage and antibiotic use (clarithromycin vs azithromycin). Statistical analysis was performed from December 23, 2019, to March 25, 2020.. Hospital admission with major hemorrhage (upper or lower gastrointestinal tract or intracranial). Outcomes were assessed within 30 days of a coprescription.. Among the 24 943 patients (12 493 women; mean [SD] age, 77.6 [7.2] years) in the study, rivaroxaban was the most commonly prescribed DOAC (9972 patients [40.0%]), followed by apixaban (7953 [31.9%]) and dabigatran (7018 [28.1%]). Coprescribing clarithromycin vs azithromycin with a DOAC was associated with a higher risk of a hospital admission with major hemorrhage (51 of 6592 patients [0.77%] taking clarithromycin vs 79 of 18 351 patients [0.43%] taking azithromycin; adjusted hazard ratio, 1.71 [95% CI, 1.20-2.45]; absolute risk difference, 0.34%). Results were consistent in multiple additional analyses.. This study suggests that, among adults of advanced age taking a DOAC, concurrent use of clarithromycin compared with azithromycin was associated with a small but statistically significantly greater 30-day risk of hospital admission with major hemorrhage.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Azithromycin; Clarithromycin; Dabigatran; Drug Interactions; Factor Xa Inhibitors; Female; Hemorrhage; Hospitalization; Humans; Male; Pyrazoles; Pyridones; Retrospective Studies; Risk Factors; Rivaroxaban

Comparative effectiveness and safety of oral anticoagulants in patients with atrial fibrillation and high polypharmacy are unknown.. We used Medicare administrative data to evaluate patients with new atrial fibrillation diagnosis from 2015 to 2017, who initiated an oral anticoagulant within 90 days of diagnosis. Patients taking ≤3, 4 to 8, or ≥9 other prescription medications were categorized as having low, moderate, or high polypharmacy, respectively. Within polypharmacy categories, patients receiving apixaban 5 mg twice daily, rivaroxaban 20 mg once daily, or warfarin were matched using a 3-way propensity score matching. Study outcomes included ischemic stroke, bleeding, and all-cause mortality.. The study cohort included 6985 patients using apixaban, 3838 using rivaroxaban, and 6639 using warfarin. In the propensity-matched cohorts there was no difference in risk of ischemic stroke between the 3 drugs in patients with low and moderate polypharmacy. However, among patients with high polypharmacy, the risk of ischemic stroke was higher with apixaban compared with warfarin (adjusted hazard ratio 2.34 [95% CI, 1.01-5.42];. Our study suggests that among patients with significant polypharmacy (>8 drugs), there may be a higher stroke and mortality risk with apixaban compared with warfarin and rivaroxaban. However, differences were of borderline significance.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Centers for Medicare and Medicaid Services, U.S.; Comparative Effectiveness Research; Female; Hemorrhage; Humans; Male; Middle Aged; Polypharmacy; Pyrazoles; Pyridones; Rivaroxaban; Stroke; United States; Warfarin

The Coronavirus Disease 2019 (COVID 19) has been reported in almost every country in the world. Although a large proportion of infected individuals develop only mild symptoms or are asymptomatic, the spectrum of the disease among others has been widely variable in severity. Additionally, many infected individuals were found to have coagulation markers abnormalities. This is especially true among those progressing to severe pneumonia and multi-organ failure. While the incidence of venous thromboembolic (VTE) disease has been recently noted to be elevated among critically ill patients, the incidence among ambulatory and non-critically ill patients is not yet clearly defined. Herein, we present six patients who didn't have any hypercoagulable risk factors yet presented with pulmonary embolism in association with COVID 19 infection. Furthermore, we discuss the possible underlying mechanisms of hypercoagulability and highlight the possibility of underdiagnosing pulmonary embolism in the setting of overlapping symptoms, decreased utilization of imaging secondary to associated risks, and increased turnover times. In addition, we emphasize the role of extended thromboprophylaxis in discharged patients.

Topics: Adult; Aged; Anticoagulants; Betacoronavirus; Coronavirus Infections; COVID-19; Enoxaparin; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Pandemics; Pneumonia, Viral; Pulmonary Embolism; Pyrazoles; Pyridones; Rivaroxaban; SARS-CoV-2; Tissue Plasminogen Activator

To investigate the association of extremes in bodyweight (EBW) and outcomes in patients with acute venous thromboembolism (VTE). Recurrent VTE, major bleeding, and clinically relevant non-major bleeding were compared between patients with bodyweight <60 kg, 60-120 kg, and >120 kg.. Consecutive patients enrolled in the Mayo Clinic VTE Registry (03/28/2013-8/31/2019) with acute VTE were followed prospectively. Patient status was assessed in person, by mailing a written questionnaire, or by a scripted phone interview.. Among 2577 patients with weight ranging from 27.0 kg to 263.2 kg, 2123 (82%) had a bodyweight between 60 and 120 kg, 223 (8.7%) had bodyweight < 60 kg, and 230 (8.9%) had bodyweight >120 kg. Patients with bodyweight <60 kg treated with DOACs had higher 3- and 6-month incidence of major bleeding compared to the bodyweight 60-120kg group (4.4% vs 1.1%, P = .03, and 4.4% vs 1.4%, P = .05, respectively). Patients with bodyweight >120 kg and cancer on rivaroxaban had higher VTE recurrence compared to bodyweight 60-120kg group (P = .01).. Treatment of acute VTE is associated with a higher incidence of bleeding in patients with bodyweight <60 kg. A higher VTE recurrence rate occurred only in cancer patients with bodyweight >120 kg on rivaroxaban.

Topics: Acute Disease; Anticoagulants; Body Weight; Disease Management; Drug Therapy, Combination; Factor Xa Inhibitors; Health Care Surveys; Hemorrhage; Humans; Pyrazoles; Pyridones; Registries; Rivaroxaban; Venous Thromboembolism

Andexanet alfa, a novel anticoagulation reversal agent for factor Xa inhibitors, was recently approved. Traumatic intracranial hemorrhage presents a prime target for this drug. The Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors study established the efficacy of andexanet alfa in reversing factor Xa inhibitors. However, the association between anticoagulation reversal and traumatic intracranial hemorrhage progression is not well understood. The objective of this study was to determine progression rates of patients with traumatic intracranial hemorrhage on factor Xa inhibitors prior to hospitalization who were managed without the use of andexanet alfa.. A retrospective cohort study was performed between 2016 and 2019 at a single institution. An institutional traumatic brain injury (TBI) registry was queried. Patients with recorded use of apixaban or rivaroxaban <18 hours before injury were included. The primary study outcome was <35% increase in hemorrhage volume or thickness on repeated head computed tomography (CT) scans.. We identified 25 patients meeting the inclusion criteria. Two patients were excluded because of a lack of necessary CT data. Twelve patients (52%) were receiving apixaban, and 11 were (48%) on rivaroxaban. On admission CT scan, 14 patients had subdural hematoma, 6 had traumatic intraparenchymal hemorrhage, and 3 had subarachnoid hemorrhage. Anticoagulation reversal was attempted in 17 patients (74%), primarily using 4-factor prothrombin complex concentrate. Twenty patients (87%) were adjudicated as having excellent or good hemostasis on repeat imaging.. Our results indicate that patients on factor Xa inhibitors with complicated mild TBI have a similar intracranial hemorrhage progression rate to patients who are not anticoagulated or anticoagulated with a reversible agent. The hemostatic outcomes in our cohort were similar to those reported after andexanet alfa administration.

Topics: Aged; Aged, 80 and over; Atrial Fibrillation; Blood Coagulation Factors; Cerebral Hemorrhage, Traumatic; Cohort Studies; Disease Progression; Factor Xa; Factor Xa Inhibitors; Female; Glasgow Coma Scale; Hematoma, Subdural, Intracranial; Hemostasis; Humans; Intracranial Hemorrhage, Traumatic; Male; Middle Aged; Plasma; Platelet Transfusion; Pyrazoles; Pyridones; Recombinant Proteins; Retrospective Studies; Risk; Risk Factors; Rivaroxaban; Subarachnoid Hemorrhage, Traumatic; Tomography, X-Ray Computed; Venous Thromboembolism

The CHA2DS2-VASc scale does not include potential risk factors for left atrial appendage thrombus (LAAT) formation such as a form of atrial fibrillation (AF) and impaired kidney function. The real risk of thromboembolic complications in AF patients is still unclear as well as an optimal anticoagulant treatment in males with a CHA2DS2-VASc score of 1 and females with a CHA2DS2-VASc score of 2.The aim of this study was to compare the predictive value of the CHA2DS2-VASc scale and other scales to estimate the risk of LAAT formation in AF patients treated with non-vitamin K oral anticoagulants (NOACs) and to assess the prevalence of thrombi in patients at intermediate risk of stroke.The observational study included consecutive patients with a diagnosis of non-valvular AF treated with NOACs, admitted to 3 high-reference institutions between 2013 and 2018. All individuals underwent transoesophageal echocardiography before cardioversion or ablation.Out of 1163 enrolled AF patients (62.1% male, mean age 62 years) the LAAT had been detected in 50 individuals (4.3%). Among patients with LAAT, 1 patient (2.0%) was classified as a low-risk category, 9 (18.0%) were at intermediate-risk, and 40 (80.0%) were at high risk of thromboembolic complications according to CHA2DS2-VASc scale. All patients were treated with NOACs: 51.0% rivaroxaban, 47.1% dabigatran, and 1.9% apixaban.Patients at intermediate stroke-risk with detected LAAT had higher R2CHADS2 score (2.1 ± 1.2 vs 1.2 ± 0.8, P = .007), higher CHA2DS2-VASc-RAF score (6.4 ± 4.4 vs 3.7 ± 2.6, P = .027) and more often had an estimated glomerular filtration rate below 56 mL/min/1.73 m (44.4% vs 13.2%, P = .026) compared to patients without LAAT. The receiver operating characteristics revealed that the CHA2DS2-VASc-RAF scale had better predictive ability to distinguish between patients with and without LAAT in the study group than CHA2DS2-VASc (P = .0006), CHADS2 (P = .0006) and R2CHADS2 scale (P = .0140).The CHA2DS2-VASc scale should be supplemented with an assessment of renal function and form of AF to improve stroke risk estimation. The application of additional scales to estimate the risk of LAAT might be especially useful among males with a CHA2DS2-VASc score of 1 and females with a CHA2DS2-VASc score of 2.

Topics: Aged; Atrial Appendage; Atrial Fibrillation; Dabigatran; Echocardiography, Transesophageal; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Risk Assessment; Risk Factors; Rivaroxaban; Thromboembolism

Current guidelines recommend anticoagulation with a vitamin K antagonist (warfarin) after a bioprosthetic valve replacement. There is minimal literature evaluating direct oral anticoagulants (DOACs) in patients who have just received a bioprosthetic aortic valve replacement (AVR) or mitral valve replacement (MVR). The purpose of this study was to investigate any differences in efficacy and safety for patients taking a DOAC, compared with warfarin, after a bioprosthetic AVR or MVR.. A retrospective cohort study was performed to evaluate anticoagulation in patients who received bioprosthetic valve replacements at a large teaching hospital from 2014 to 2018. Patients included in this study received either warfarin or a DOAC following bioprosthetic AVR or MVR, and were maintained on the same agent throughout the 6-month follow-up period. The primary efficacy outcome was the incidence of thromboembolic complications and the primary safety outcome was the incidence of major bleeding within 6 months following surgery. The rate of readmission was assessed as a secondary endpoint.. A total of 197 patients were included; 70 patients received warfarin and 127 patients received a DOAC (apixaban, n = 86; rivaroxaban, n = 40; dabigatran, n = 1). Three patients experienced thromboembolic events, all of which occurred in the DOAC group (0% vs. 2.4%; p = 0.20). Major bleeding occurred in 11 patients-two in the warfarin group and nine in the DOAC group (2.9% vs. 7.1%; p = 0.22). Sixty-one patients were readmitted within the 6-month time frame, with 26 readmissions in the warfarin group and 35 readmissions in the DOAC group (37% vs. 27%; p = 0.16).. This small, exploratory study found similar rates of thromboembolic complications and major bleeding events in patients who received a DOAC versus warfarin after a recent bioprosthetic AVR or MVR. This study was limited by its retrospective nature and its sample size. Larger, randomized controlled trials are needed to further determine the efficacy and safety of DOACs in this patient population.

Topics: Administration, Oral; Aged; Anticoagulants; Bioprosthesis; Dabigatran; Female; Heart Valve Prosthesis; Hemorrhage; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Thromboembolism; Warfarin

The efficacy and safety of the direct oral anticoagulants (DOACs) in fragile patients (age ≥ 75 years and/or creatinine clearance [CrCl] levels ≤50 mL/min and/or body weight ≤50kg) with venous thromboembolism (VTE) have not been consistently compared.. We used the RIETE database to compare the rates of the composite of VTE recurrences or major bleeding during anticoagulation in fragile patients with VTE, according to the use of rivaroxaban or apixaban for initial and long-term therapy.. From January 2013 to October 2019, 36,889 patients were recruited, of whom 14,831 (40%) were fragile. Overall, 999 fragile patients (15%) received DOACs starting within the first 48 h: rivaroxaban 711 and apixaban 288. Median duration of therapy was: 113 vs. 111 days. A substantial amount of patients in both subgroups (25% vs. 40%) received non-recommended doses of DOACs. During anticoagulation, 13 patients developed VTE recurrences, 18 had major bleeding and 36 died. When only considering patients receiving recommended doses (n = 705), there were no differences between drugs in the rate of the composite outcome (rate ratio [RR]: 1.08; 95%CI: 0.35-3.30) or all-cause death (RR: 0.99; 95%CI: 0.32-3.08). On multivariable analysis, patients receiving rivaroxaban or apixaban at recommended doses had a similar risk for the composite outcome (hazard ratio: 1.34; 95%CI: 0.35-5.06).. The use of rivaroxaban or apixaban at recommended doses in fragile patients with VTE was associated with a similar risk for VTE recurrences or major bleeding.

Topics: Administration, Oral; Aged; Anticoagulants; Humans; Pyrazoles; Pyridones; Rivaroxaban; Treatment Outcome; Venous Thromboembolism

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

Topics: Acute Coronary Syndrome; Acute Disease; Aspirin; Atrial Fibrillation; Clopidogrel; Combined Modality Therapy; Cyclophosphamide; Dabigatran; Drug Therapy, Combination; Fibrinolytic Agents; Hemorrhage; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Risk Factors; Rivaroxaban; Stents; Stroke; Vitamin K

Insufficient real-world data on acute liver injury (ALI) risk associated with oral anticoagulants (OACs) exist in patients with nonvalvular atrial fibrillation (NVAF). Using the French national healthcare databases, a propensity-weighted nationwide cohort study was performed in NVAF patients initiating OACs from 2011 to 2016, considering separately those (1) with no prior liver disease (PLD) as main population, (2) with PLD, (3) with a history of chronic alcoholism. A Cox proportional hazards model was used to estimate the hazard ratio with 95% confidence interval (HR [95% CI]) of serious ALI (hospitalised ALI or liver transplantation) during the first year of treatment, for each non-vitamin K antagonist (VKA) oral anticoagulant (NOAC: dabigatran, rivaroxaban, apixaban) versus VKA. In patients with no PLD (N = 434,015), only rivaroxaban new users were at increased risk of serious ALI compared to VKA initiation (adjusted HR: 1.41 [1.05-1.91]). In patients with chronic alcoholism history (N = 13,173), only those initiating dabigatran were at increased risk of serious ALI compared to VKA (2.88 [1.74-4.76]) but an ancillary outcome suggested that differential clinical follow-up between groups might partly explain this association. In conclusion, this study does not suggest an increase of the 1-year risk of ALI in NOAC versus VKA patients with AF.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Alcoholism; Anticoagulants; Atrial Fibrillation; Cohort Studies; Dabigatran; Female; France; Humans; Liver Failure, Acute; Male; Middle Aged; Propensity Score; Proportional Hazards Models; Pyrazoles; Pyridones; Risk; Rivaroxaban; Young Adult

Direct oral anticoagulants (DOACs) have promised superior efficacy to low molecular weight heparins in the prevention of venous thromboembolism (VTE) in total hip and knee arthroplasty. However, there are concerns about raised associated bleeding and wound problems with these agents. This study aims to evaluate and compare the efficacy and safety of the 3 DOAC drugs: rivaroxaban, dabigatran and apixaban.. The primary outcome measures were rate of symptomatic VTE and major bleeding. Secondary outcome measures were wound healing problems and requirement for return to theater. A total of 2431 patients received one of the DOAC drugs as thromboprophylaxis following total hip arthroplasty (35 days) or total knee arthroplasty (14 days) between 2011 and 2015. Binary variables were compared between the 3 groups by using the chi-squared test or Fisher's exact test. Relative risks of selected primary and secondary end points were also calculated for the prespecified pairwise comparison.. The overall symptomatic VTE rate was 2%. Rivaroxaban had a statistically significant superior efficacy for overall VTE prevention (0.8% vs 2.6%) compared with dabigatran (P < .01) and apixaban (P < .01), and deep vein thrombosis prevention (0.3% vs 2.2%) over dabigatran (P < .01). The overall rate of major bleeding was 1.2% with no significant difference observed between the 3 studied drugs.. All 3 drugs had symptomatic VTE rates comparable with low molecular weight heparin from the published literature. Rivaroxaban appears to have superior efficacy in VTE prevention over apixaban and dabigatran. No statistical difference was observed for major bleeding with any of the 3 agents.

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Dabigatran; Humans; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban; Venous Thromboembolism

Little is known about the impact of oral anticoagulation (OAC) choice on healthcare encounters during venous thromboembolism (VTE) primary treatment. Among anticoagulant-naïve patients with VTE, we tested the hypotheses that healthcare utilization would be lower among users of direct OACs (DOACs; rivaroxaban or apixaban) than among users of warfarin. MarketScan databases for years 2016 and 2017 were used; healthcare utilization was identified in the first 6 months after initial VTE diagnoses. The 23,864 patients with VTE had on average 0.2 ± 0.5 hospitalizations, spent 1.3 ± 5.2 days in the hospital, had 5.7 ± 5.1 outpatient encounters, and visited an emergency department 0.4 ± 1.1 times. As compared to warfarin, rivaroxaban and apixaban were associated with fewer hospitalizations, days hospitalized, outpatient office visits, and emergency department visits after accounting for age, sex, comorbidities, and medications. Hospitalization rates were 24% lower (incidence rate ratio (IRR): 0.76; 95% CI: 0.69, 0.83) with rivaroxaban and 22% lower (IRR: 0.78; 95% CI: 0.71, 0.87) with apixaban, as compared to warfarin (IRR: 1.00 (reference)). Healthcare utilization was similar between apixaban and rivaroxaban users. Patients with VTE prescribed rivaroxaban and apixaban had lower healthcare utilization than those prescribed warfarin, while there was no difference when comparing apixaban to rivaroxaban. These findings complement existing literature supporting the use of DOACs over warfarin.

Topics: Administration, Oral; Adult; Aged; Ambulatory Care; Anticoagulants; Databases, Factual; Emergency Service, Hospital; Factor Xa Inhibitors; Female; Health Resources; Hospitalization; Humans; Male; Middle Aged; Office Visits; Pyrazoles; Pyridones; Rivaroxaban; Time Factors; Treatment Outcome; United States; Venous Thromboembolism; Warfarin

To determine a patient's clinical course based on the use of an activated partial thromboplastin time (aPTT) or heparin anti-Xa assay when transitioning from rivaroxaban or apixaban to an unfractionated heparin infusion.. A retrospective chart review was conducted to investigate how unfractionated heparin infusions were managed at a tertiary care hospital in the setting of recent apixaban or rivaroxaban administration. Patients were separated into 2 cohorts based on the chosen heparin infusion monitoring assay: heparin anti-Xa or aPTT. The primary composite outcome was total number of bleeding and thrombotic events; the secondary composite outcome was average incidence of heparin infusion holds and rate changes per patient.. Data were collected from 76 patients (heparin anti-Xa = 69, aPTT = 7). Due to the limited number of patients within the aPTT cohort, this data was excluded from the analysis, and heparin anti-Xa descriptive statistics were reported without statistical comparisons. In the heparin anti-Xa group, a total of 10 bleeds and 1 thrombus were discovered. Additionally, the average number of infusion holds and rate changes was 0.841 and 2.65 times per patient, respectively, for those patients monitored via heparin anti-Xa assay.. In the presence of a recently administered oral anti-Xa anticoagulant, more down-titrations occurred in the initial 6 hours of the heparin infusion when measuring anti-Xa activity, and most up-titrations occurred after 36 hours. Baseline heparin anti-Xa activity may be a useful tool to identify patients with residual plasma concentrations of apixaban and rivaroxaban to help better individualize heparin therapy.

Topics: Aged; Anticoagulants; Cohort Studies; Drug Monitoring; Factor Xa Inhibitors; Hemorrhage; Heparin; Hospitalization; Humans; Infusions, Intravenous; Middle Aged; Partial Thromboplastin Time; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Tertiary Care Centers; Time Factors

The development of leukocytoclastic vasculitis (LCV) during apixaban therapy in a female patient being treated for deep vein thrombosis (DVT) is reported.. A 74-year-old Caucasian woman weighing 102 kg presented to a walk-in clinic with complaints of mild pain and swelling in her left leg for 2 weeks. She was diagnosed as having left lower-extremity DVT. The direct oral anticoagulant (DOAC) apixaban (10 mg twice daily for 7 days, then 5 mg twice daily for 3 months) was prescribed. At 1-week follow-up the patient stated that her DVT symptoms were slowly improving and reported that small areas of red rash had appeared bilaterally on her lower extremities. On day 23 of apixaban therapy, the patient presented to a walk-in clinic with a complaint that the rash had progressively worsened. The rash was diagnosed as LCV by dermatology consult. On day 24 of therapy, apixaban use was discontinued and the patient was initiated on rivaroxaban (20 mg daily) for the remainder of DVT treatment. LCV was found to be progressively improving on day 73, with trace petechiae. Rivaroxaban was used through the end of DVT treatment without further reports of LCV.. A female patient who developed LCV while taking apixaban for treatment of DVT was successfully transitioned to rivaroxaban therapy, leading to resolution of LCV and successful completion of DVT treatment without recurrence of LCV.

Topics: Aged; Factor Xa Inhibitors; Female; Follow-Up Studies; Humans; Pyrazoles; Pyridones; Rivaroxaban; Vasculitis, Leukocytoclastic, Cutaneous; Venous Thrombosis

Topics: Administration, Oral; Anticoagulants; Factor Xa Inhibitors; Humans; Pyrazoles; Pyridones; Rivaroxaban; Thrombophilia; Venous Thromboembolism

Topics: Atrial Fibrillation; Humans; Pyrazoles; Pyridones; Rivaroxaban; Stroke

Topics: Atrial Fibrillation; Humans; Pyrazoles; Pyridones; Rivaroxaban; Stroke

The results of randomised clinical trials (RCTs) on direct oral anticoagulants (DOACs) for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) can mostly be applied to primary prevention in relatively young patients, since only a minority of patients included in these trials were receiving DOACs for secondary prevention. The real-life secondary prevention subgroup, comprising mostly elderly and high-risk patients, remains a point of interest where further exploration is needed. Our objective was to explore the effectiveness and safety of DOACs for secondary prevention in the real-life conditions.. In a six-year (2012-2018) period all consecutive patients with a history of transient ischaemic attack (TIA) or stroke, recorded NVAF and prescription of DOAC, were included in this single-centre registry. Choice of the DOAC and dose was based on the discretion of the attending clinician. Data regarding recurrent stroke/TIA or other embolic events, intracranial haemorrhage, other major bleeding, adherence and potential changes of therapy were collected and analysed.. During the study period, 566 patients were prescribed a DOAC for secondary stroke prevention, and follow-up data were available for 510 patients, with an average observational time of 2.6 years. The mean age of patients was 77.9 ± 8.7 years. The mean CHA. Our real-life data study suggests that secondary stroke prevention with DOACs is as effective and safe as primary prevention, both in standard and reduced doses, in a typical group of patients who are older than patients included in RCTs.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Embolism; Female; Hemorrhage; Humans; Incidence; Ischemic Attack, Transient; Male; Middle Aged; Pyrazoles; Pyridones; Registries; Rivaroxaban; Secondary Prevention; Stroke

To provide the most current assessment of real-world healthcare resource utilization (HRU) and costs among patients with non-valvular atrial fibrillation (NVAF) who newly initiated rivaroxaban and apixaban using a large US database.. A retrospective weighted cohort design was used with healthcare insurance claims from the Optum Clinformatics Data Mart databases (January 2012-December 2018). The index date was defined as the first dispensing of rivaroxaban or apixaban. Adult NVAF patients with an index date on or after 1 January 2016, ≥ 12 months of continuous eligibility before the index date and ≥ 1 month after, and without prior use of oral anticoagulant were included. The observation period spanned from the index date to the earliest of the end of data availability, end of insurance coverage, or death. Inverse probability of treatment weighting (IPTW) was used to adjust for differences in baseline characteristics between cohorts. All-cause healthcare resource utilization (HRU), including hospitalization, emergency room, and outpatient visits, and healthcare costs, including medical and pharmacy costs, were evaluated from the payer's perspective during the observation period up to 18 and 24 months, separately.. In this large retrospective analysis, patients with NVAF initiated on rivaroxaban incurred significantly lower healthcare costs compared to those initiated on apixaban, which were primarily driven by significantly lower outpatient visits and costs during the 18- and 24-month follow-up periods.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Female; Health Expenditures; Humans; Insurance Claim Review; Male; Patient Acceptance of Health Care; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; United States

There is little data on management and outcomes of atrial fibrillation (AF) patients on direct oral anticoagulants (DOAC) undergoing general surgery.We retrospectively assessed 98 surgeries in 85 nonvalvular AF patients aged 73 ± 8 (59 men) receiving DOACs. Cardiac, emergency, and minimally invasive surgeries were excluded.The CHA

Topics: Aged; Aged, 80 and over; Antithrombins; Atrial Fibrillation; Blood Loss, Surgical; Carotid Artery Diseases; Cerebral Infarction; Dabigatran; Digestive System Surgical Procedures; Elective Surgical Procedures; Embolism; Endoscopy; Factor Xa Inhibitors; Female; Humans; Male; Myocardial Infarction; Orthopedic Procedures; Perioperative Care; Postoperative Complications; Postoperative Hemorrhage; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Rivaroxaban; Thiazoles; Thromboembolism; Urologic Surgical Procedures; Vascular Surgical Procedures

Oral factor Xa inhibitors (FXaI) can be administered in fixed doses without the need for routine laboratory monitoring. Anti-Xa assays can estimate anticoagulant effect for specific FXaI's. The aim of this study was to characterize anti-Xa levels in patients taking apixaban or rivaroxaban with major bleeding events.. Apixaban and rivaroxaban anti-Xa assays ordered within our hospital system from May 2016 to September 2019 were evaluated. The primary outcome was major bleeding events defined by International Society of Thrombosis and Haemostasis criteria. Median anti-Xa levels for each FXaI were calculated for those with and without major bleeding, as well as those who did and did not receive reversal agents.. A total of 606 anti-Xa levels were analyzed. There were 146 major bleeding events documented, with the most common site being intracranial (63%). Median anti-Xa levels in patients with and without major bleeding were similar, whereas those on apixaban therapy who received reversal agents typically had higher anti-Xa levels (73 ng/mL vs. 153 ng/mL, p = 0.0019). Factors significantly associated with increased odds of bleeding were an age > 80 years, inappropriately high dosing regimens, and modest anti-Xa levels (100-300 ng/mL) for rivaroxaban specifically.. Older age and inappropriately high dosing regimens were associated with major bleeding in patients taking apixaban and rivaroxaban. Further investigation into the utility of anti-Xa levels for FXaI is warranted.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Factor Xa Inhibitors; Hemorrhage; Humans; Pyrazoles; Pyridones; Rivaroxaban

Topics: Aged; Atrial Fibrillation; Blood Loss, Surgical; Dabigatran; Elective Surgical Procedures; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Medication Therapy Management; Perioperative Care; Pyrazoles; Pyridones; Risk Adjustment; Rivaroxaban; Stroke

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

Direct oral anticoagulants, such as apixaban and rivaroxaban, are important for the treatment and prophylaxis of venous thromboembolism and to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Because apixaban and rivaroxaban are predominantly eliminated by cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), concomitant use of combined P-gp and strong CYP3A4 inhibitors and inducers should be avoided. Physiologically-based pharmacokinetic models for apixaban and rivaroxaban were developed to estimate the net effect of CYP3A induction, P-gp inhibition, and P-gp induction by rifampicin. The disposition of rivaroxaban is more complex compared with apixaban because both hepatic and renal P-gp is considered to contribute to rivaroxaban elimination. Furthermore, organic anion transporter-3, a renal uptake transporter, may also contribute the elimination of rivaroxaban from systemic circulation. The models were verified with observed clinical drug-drug interactions with CYP3A and P-gp inhibitors. With the developed models, the predicted area under the concentration time curve and maximum concentration ratios were 0.43 and 0.48, respectively, for apixaban, and 0.50-0.52 and 0.72-0.73, respectively, for rivaroxaban when coadministered with 600 mg multiple doses of rifampicin and that were very close to observed data. The impact of each of the elimination pathways was assessed for rivaroxaban, and inhibition of CYP3A led to a larger impact over intestinal and hepatic P-gp. Inhibition of renal organic anion transporter-3 or P-gp led to an overall modest interaction. The developed apixaban and rivaroxaban models can be further applied to the investigation of interactions with other P-gp and/or CYP3A4 inhibitors and inducers.

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Atrial Fibrillation; Biological Transport; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Embolism; Factor Xa Inhibitors; Humans; Pyrazoles; Pyridones; Rifampin; Rivaroxaban; Stroke; Venous Thromboembolism

Controversy exists regarding first-line use of the recently approved reversal agent andexanet alfa due to limitations of the ANEXXA-4 study, thrombotic risks, and high medication acquisition cost. The purpose of this study was to evaluate the safety and effectiveness of 4F-PCC for the reversal of emergent oral fXa inhibitor-related bleeding. Furthermore, we aimed to evaluate a subgroup using strict ANNEXA-4 patient selection criteria.. This was a retrospective study conducted utilizing chart review of adult patients that received 4F-PCC for oral fXa inhibitor-related bleeding. The primary endpoint was the rate of clinical success defined as achieving excellent or good hemostatic effectiveness following the administration of 4F-PCC. Secondary endpoints included in-hospital mortality and arterial/venous thromboembolism, and cost compared with andexanet alfa.. A total of 119 patients were included, with 83 patients in the ANNEXA-4 criteria subgroup. Eighty-five of the 119 patients (71%) required reversal due to intracranial bleeding. Prior to reversal, 70 patients (59%) were taking apixaban and 49 patients (41%) were taking rivaroxaban. Clinical success was achieved in 106 of 119 patients (89%) and 74 of 83 patients (90%) in the strict criteria subgroup. Three of 119 patients (2.5%) had a thrombotic event during hospital stay and the overall mortality rate was 13%. The average cost increase of andexanet alfa compared to 4F-PCC would have been $29,500 per patient.. Administration of 4F-PCC for the reversal of oral fXa inhibitors was effective with relatively low thrombotic risk. Further direct prospective comparison of 4F-PCC to andexanet alfa is warranted.

Topics: Aged; Aged, 80 and over; Antidotes; Blood Coagulation Factors; Drug Costs; Emergencies; Factor Xa; Factor Xa Inhibitors; Female; Gastrointestinal Hemorrhage; Hemorrhage; Hospital Mortality; Humans; Intracranial Hemorrhages; Male; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban; Thromboembolism; Treatment Outcome

Topics: Aged; Aged, 80 and over; Anticoagulants; Aspirin; Blood Coagulation Factors; Cerebral Hemorrhage, Traumatic; Cerebral Intraventricular Hemorrhage; Clopidogrel; Deamino Arginine Vasopressin; Female; Fractures, Bone; Hematoma; Hematoma, Subdural, Intracranial; Hemostatics; Humans; International Normalized Ratio; Intracranial Hemorrhage, Traumatic; Male; Middle Aged; Pelvic Bones; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Subarachnoid Hemorrhage, Traumatic; Thrombosis; Warfarin

To investigate the differences in the characteristics and clinical outcomes of recently diagnosed patients with atrial fibrillation (AF) receiving different types of anticoagulants in a real-life setting.. We retrospectively analyzed the charts of 1000 consecutive patients with non-valvular AF diagnosed at our institution or referred it to from 2013 to 2018.. Over the observed period, the frequency of direct oral anticoagulation (DOAC) therapy use significantly increased (P = 0.002). Patients receiving warfarin had more unfavorable thromboembolic and bleeding risk factors than patients receiving DOAC. Predetermined stroke and major bleeding risks were similarly distributed among the dabigatran, rivaroxaban, and apixaban groups. Patients receiving warfarin had shorter time-to-major bleeding (TTB), time to thrombosis (TTT), and overall survival (OS) than patients receiving DOACs. After adjustment for factors unbalanced at baseline, the warfarin group showed significantly shorter OS (hazard ratio 2.27, 95% confidence interval 1.44-3.57, P<0.001], while TTB and TTT did not significantly differ between the groups. Only 37% of patients on warfarin had optimal dosing control, and they did not differ significantly in TTB, TTT, and OS from patients on DOACs.. Warfarin and DOACs are administered to different target populations, possibly due to socio-economic reasons. Patients receiving warfarin rarely obtain optimal dosing control, and experience significantly shorter survival compared with patients receiving DOACs.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Proportional Hazards Models; Pyrazoles; Pyridones; Registries; Retrospective Studies; Risk Factors; Rivaroxaban; Stroke; Survival Rate; Warfarin; Young Adult

Atrial fibrillation (AF) is associated with increased stroke and bleeding risk in patients with chronic kidney disease (CKD). Little is known about the real-life use of non-vitamin K antagonist oral anticoagulants (NOACs) in CKD stage G4. In a retrospective cohort study, we enrolled 182 consecutive AF patients with CKD stage G4 including 90 (49%) subjects on NOAC, ie, 61 on apixaban 2.5 mg bid and 29 on rivaroxaban 15 mg qd, and 92 (51%) subjects on warfarin. Thromboembolic and bleeding events were recorded during a mean follow-up of 26.3 months. There were no differences in demographic, clinical, and laboratory variables at baseline between the 2 treatment groups. During follow-up, arterial thromboembolic events occurred in 11 (12.22%) subjects on NOAC and 7 (7.61%) on warfarin, (hazard ratio [HR] 1.70; 95% CI, 0.65-4.42), with similar risk of ischemic stroke (9 [10%] vs. 7 [7.61%], P = 0.56, respectively). Major bleedings or clinically relevant nonmajor bleeding occurred in 14 (15.56%) on NOAC and 13 (14.13%) on warfarin, (HR 1.12; 95% CI, 0.53-2.39), with similar risk of gastrointestinal bleeding (HR 0.70; 95% CI, 0.20-2.47). We observed no difference in all-cause mortality related to the type of anticoagulants, but it tended to be lower in the apixaban group compared with rivaroxaban group (14.7% vs. 31%, P = 0.07), without any differences in thromboembolic and bleeding events. The study suggests that AF patients with CKD stage G4 receiving reduced-dose NOAC or warfarin have similar risk of thromboembolism and bleeding in everyday practice of a tertiary anticoagulation center.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Poland; Pyrazoles; Pyridones; Renal Insufficiency, Chronic; Retrospective Studies; Risk Assessment; Risk Factors; Rivaroxaban; Severity of Illness Index; Stroke; Thromboembolism; Time Factors; Treatment Outcome; Warfarin

Topics: Aftercare; Anticoagulants; Benzamides; Duration of Therapy; Enoxaparin; Heparin, Low-Molecular-Weight; Hospitalization; Humans; Length of Stay; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Venous Thromboembolism; Venous Thrombosis

This study aims to measure the plasma levels of rivaroxaban and apixaban among Asian patients with atrial fibrillation and compare the results with expected drug levels from clinical studies. A total of 73 patients taking rivaroxaban and 105 patients taking apixaban were enrolled. Peak and trough levels were measured using ultra-high performance liquid chromatography with tandem mass spectrometry. The percentage of those with drug levels within the expected range reported in clinical studies was significantly higher in the apixaban group than in the rivaroxaban group, both for trough (84.8% vs. 64.4%; P = 0.002) and peak levels (76.9% vs. 33.8%; P < 0.001). After adjusting for age, sex, kidney function, appropriate dose, and adherence, patients taking rivaroxaban were still less likely to have peak and trough levels within the expected drug levels. Our real-world data suggests that Asian patients taking rivaroxaban are more likely to have out-of-expected drug levels than those taking apixaban.

Topics: Aged; Aged, 80 and over; Asian People; Atrial Fibrillation; Chromatography, High Pressure Liquid; Factor Xa Inhibitors; Female; Humans; Male; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban; Tandem Mass Spectrometry

The purpose of the study was to examine the association between the type of preceding oral anticoagulant use (warfarin or direct oral anticoagulants [DOACs]) and in-hospital mortality among patients admitted with gastrointestinal bleeding.. In this observational cohort study, all patients admitted with a first-time gastrointestinal bleeding from January 2011 to March 2017 while receiving any oral anticoagulant therapy prior to admission were identified using data from Danish nationwide registries. The risk of in-hospital mortality according to type of oral anticoagulation therapy was examined by multivariable logistic regression models.. Among 5,774 patients admitted with gastrointestinal bleeding (median age, 78 years [25th-75th percentile, 71-85 years]; 56.8% men), 2,038 (35.3%) were receiving DOACs and 3,736 (64.7%) were receiving warfarin prior to admission. The unadjusted in-hospital mortality rates were 7.5% for DOAC (7.2% for dabigatran, 6.4% for rivaroxaban, and 10.1% for apixaban) and 6.5% for warfarin. After adjustment for baseline demographic and clinical characteristics, there was no statistically significant difference in in-hospital mortality between prior use of any DOAC and warfarin (unadjusted odds ratio [OR] 1.18 [95% CI 0.95-1.45], adjusted OR 0.97 [95% CI 0.77-1.24]). Similar results were found for each individual DOAC as compared with warfarin (dabigatran: unadjusted OR 1.12 [95% CI 0.84-1.49], adjusted OR 0.96 [95% CI 0.71-1.30]); rivaroxaban: unadjusted OR 0.98 [95% CI 0.71-1.37], adjusted OR 0.84 [95% CI 0.59-1.21]; and apixaban: unadjusted OR 1.62 [95% CI 0.84-1.49], adjusted OR 1.22 [95% CI 0.83-1.79]).. Among patients admitted with gastrointestinal bleeding, there was no statistically significant difference in in-hospital mortality between prior use of DOAC and warfarin.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Cohort Studies; Dabigatran; Denmark; Female; Gastrointestinal Hemorrhage; Hospital Mortality; Humans; Logistic Models; Male; Pyrazoles; Pyridones; Rivaroxaban; United States; Vitamin K; Warfarin

Topics: Anticoagulants; Cost-Benefit Analysis; Female; Health Expenditures; Health Resources; Humans; Male; Markov Chains; Middle Aged; Models, Econometric; Network Meta-Analysis; Pyrazoles; Pyridones; Quality-Adjusted Life Years; Rivaroxaban; United Kingdom; Venous Thromboembolism

To describe the nature, frequency and content of non-vitamin K oral anticoagulant (NOAC)-related events for healthcare professionals sponsored by the manufacturers of the NOACs in Australia. A secondary objective is to compare these data to the rate of dispensing of the NOACs in Australia.. This cross-sectional study examined consolidated data from publicly available Australian pharmaceutical industry transparency reports from October 2011 to September 2015 on NOAC-related educational events. Data from April 2011 to June 2016 on NOAC dispensing, subsidised under Australia's Pharmaceutical Benefits Scheme (PBS), were obtained from the Department of Health and the Department of Human Services.. Characteristics of NOAC-related educational events including costs (in Australian dollars, $A), numbers of events, information on healthcare professional attendees and content of events; and NOAC dispensing rates.. During the study period, there were 2797 NOAC-related events, costing manufacturers a total of $A10 578 745. Total expenditure for meals and beverages at all events was $A4 238 962. Events were predominantly attended by general practitioners (42%, 1174/2797), cardiologists (35%, 977/2797) and haematologists (23%, 635/2797). About 48% (1347/2797) of events were held in non-clinical settings, mainly restaurants, bars and cafes. Around 55% (1551/2797) of events consisted of either conferences, meetings or seminars. The analysis of the content presented at two events detected promotion of NOACs for unapproved indications, an emphasis on a favourable benefit/harm profile, and that all speakers had close ties with the manufacturers of the NOACs. Following PBS listings relevant to each NOAC, the numbers of events related to that NOAC and the prescribing of that NOAC increased.. Our findings suggest that the substantial investment in NOAC-related events made by four pharmaceutical companies had a promotional purpose. Healthcare professionals should seek independent information on newly subsidised medicines from, for example, government agencies or drug bulletins.

Topics: Anticoagulants; Australia; Cross-Sectional Studies; Dabigatran; Drug Industry; Education, Medical, Continuing; Humans; Practice Patterns, Physicians'; Pyrazoles; Pyridones; Rivaroxaban

To compare effectiveness and safety of warfarin and the direct oral anticoagulants (DOAC) dabigatran, rivaroxaban and apixaban in non-valvular atrial fibrillation in routine care.. From nationwide registries, we identified treatment-naïve patients initiating warfarin, dabigatran, rivaroxaban or apixaban for non-valvular atrial fibrillation from July 2013 to December 2015 in Norway. We assessed prescription duration using reverse waiting time distribution. Adjusting for confounding in a Cox proportional hazards model, we estimated one-year risks for ischemic stroke, transient ischemic attack (TIA) or systemic embolism, major or clinically relevant non-major bleeding; intracranial; gastrointestinal; and other bleeding. We censored at switch of treatment or 365 days of follow-up.. We included 30,820 treatment-naïve patients. Compared to warfarin, the adjusted hazard ratios (HR) for ischemic stroke, TIA or systemic embolism were 0.96 (95% CI 0.71-1.28) for dabigatran, 1.12 (95% CI 0.87-1.45) for rivaroxaban and 0.97 (95% CI 0.75-1.26) for apixaban. Corresponding hazard ratios for major or clinically relevant non-major bleeding were 0.73 (95% CI 0.62-0.86) for dabigatran, 0.97 (95% CI 0.84-1.12) for rivaroxaban and 0.71 (95% CI 0.62-0.82) for apixaban. Statistically significant differences of other safety outcomes compared to warfarin were fewer intracranial bleedings with dabigatran (HR 0.28, 95% CI 0.14-0.56), rivaroxaban (HR 0.40, 95% CI 0.23-0.69) and apixaban (HR 0.56, 95% CI 0.34-0.92); fewer gastrointestinal bleedings with apixaban (HR 0.70, 95% CI 0.52-0.93); and fewer other bleedings with dabigatran (HR 0.67, 95% CI 0.55-0.81) and apixaban (HR 0.70, 95% CI 0.59-0.83).. After 1 year follow-up in treatment-naïve patients initiating oral anticoagulation for non-valvular atrial fibrillation, all DOACs were similarly effective as warfarin in prevention of ischemic stroke, TIA or systemic embolism. Safety from bleedings was similar or better, including fewer intracranial bleedings with all direct oral anticoagulants, fewer gastrointestinal bleedings with apixaban and fewer other bleedings with dabigatran and apixaban.

Topics: Aged; Atrial Fibrillation; Dabigatran; Female; Follow-Up Studies; Humans; Male; Pyrazoles; Pyridones; Rivaroxaban; Treatment Outcome; Warfarin

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

Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular dysplasia resulting in visceral arteriovenous malformations and smaller mucocutaneous telangiectasia. Most patients experience recurrent nosebleeds and become anemic without iron supplementation. However, thousands may require anticoagulation for conditions such as venous thromboembolism and/or atrial fibrillation. Over decades, tolerance data has been published for almost 200 HHT-affected users of warfarin and heparins, but there are no published data for the newer direct oral anticoagulants (DOACs) in HHT.. To provide such data, a retrospective audit was conducted across the eight HHT centres of the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN), in Denmark, France, Germany, Italy, the Netherlands and the UK.. Although HHT Centres had not specifically recommended the use of DOACs, 32 treatment episodes had been initiated by other clinicians in 28 patients reviewed at the Centres, at median age 65 years (range 30-84). Indications were for atrial fibrillation (16 treatment episodes) and venous thromboembolism (16 episodes). The 32 treatment episodes used Apixaban (n = 15), Rivaroxaban (n = 14), and Dabigatran (n = 3). HHT nosebleeds increased in severity in 24/32 treatment episodes (75%), leading to treatment discontinuation in 11 (34.4%). Treatment discontinuation was required for 4/15 (26.7%) Apixaban episodes and 7/14 (50%) Rivaroxaban episodes. By a 4 point scale of increasing severity, there was a trend for Rivaroxaban to be associated with a greater bleeding risk both including and excluding patients who had used more than one agent (age-adjusted coefficients 0.61 (95% confidence intervals 0.11, 1.20) and 0.74 (95% confidence intervals 0.12, 1.36) respectively. Associations were maintained after adjustment for gender and treatment indication. Extreme hemorrhagic responses, worse than anything experienced previously, with individual nosebleeds lasting hours requiring hospital admissions, blood transfusions and in all cases treatment discontinuation, occurred in 5/14 (35.7%) Rivaroxaban episodes compared to 3/15 (20%) Apixaban episodes and published rates of ~ 5% for warfarin and heparin.. Currently, conventional heparin and warfarin remain first choice anticoagulants in HHT. If newer anticoagulants are considered, although study numbers are small, at this stage Apixaban appears to be associated with lesser bleeding risk than Rivaroxaban.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Epistaxis; Female; Humans; Male; Middle Aged; Pulmonary Embolism; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Telangiectasia, Hereditary Hemorrhagic; Venous Thromboembolism; Warfarin

Direct oral anticoagulants (DOACs) were developed to overcome some of the limitations associated with vitamin K antagonists (VKAs), such as interindividual variability or the need for therapeutic drug monitoring. However, the complexity of DOAC dose regimens can still lead to dosing errors and potential bleeding-related or thromboembolic adverse events, especially in the elderly.. Our objective was to evaluate the rate of inappropriate preadmission DOAC prescriptions at hospital and to evaluate the ability of hospitals to correct them.. An observational prospective study was conducted in elderly patients (aged ≥ 65 years) hospitalized in six acute units of three Parisian university hospitals between February and July 2018. DOAC prescriptions prior to admission and at discharge were analyzed according to the guidelines in the summaries of product characteristics.. A total of 157 patients were included in the study, with a median age of 84 years (interquartile range [IQR] 77-89). The median glomerular filtration rate, determined with the Cockcroft-Gault equation, was 48 mL/min (IQR 35-61). Apixaban was the most frequently prescribed drug, mainly for atrial fibrillation. Overall, 48 (30.6%) and 34 (22.4%) prescriptions were inappropriate prior to admission and at discharge, respectively, showing a significant decrease (p < 0.001). Hospitals significantly corrected more inappropriate prescriptions (37.5%) than they generated (4.6%) (p < 0.05). The nature of the inappropriate prescribing was underdosing (68.8% and 76.5% prior to admission and at discharge, respectively), followed by overdosing (stable rate at almost 20%) and indication errors. No risk factors for inappropriate use were identified by our analysis.. One-third of DOAC preadmission prescriptions for elderly patients were inappropriate, indicating that a need remains to strengthen DOAC prescribing guidelines in ambulatory clinical practice. However, the rate of inappropriate prescriptions decreased at patient discharge. Future studies are needed to test actions to promote the proper use of DOACs.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Female; France; Hemorrhage; Hospitalization; Humans; Inappropriate Prescribing; Male; Patient Admission; Patient Discharge; Prospective Studies; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Thromboembolism

To evaluate the appropriateness of the initial prescribed daily dose of non-vitamin K antagonist oral anticoagulants (NOACs) according to label in patients with non-valvular atrial fibrillation (NVAF) in the UK.. Population-based cross-sectional study.. UK primary care.. 30 467 patients with NVAF and a first prescription for apixaban, dabigatran or rivaroxaban between January 2011 and December 2016.. Percentage of patients prescribed a NOAC dose according to the European Union (EU) labels (appropriately dosed), and not according to the EU labels (inappropriately dosed-including both underdosed and overdosed patients); percentage of patients prescribed an initial NOAC dose according to renal function status.. A total of 15 252 (50.1%) patients started NOAC therapy on rivaroxaban, 10 834 (35.6%) on apixaban and 4381 (14.4%) on dabigatran. Among patients starting NOAC therapy on rivaroxaban, 17.3% were eligible to receive a reduced dose compared with 12.8% of patients starting on apixaban and 53.8% of patients starting on dabigatran. The majority of patients were prescribed an appropriate dose according to the EU labels: apixaban 74.9 %, dabigatran, 74.4%; rivaroxaban, 84.2%. Underdosing occurred in 21.6% (apixaban), 8.7% (dabigatran), 9.1% (rivaroxaban). Overdosing was more frequent for dabigatran (16.9%) than for rivaroxaban (6.6%) or apixaban (3.5%). There was a trend towards dose reduction with increasing renal impairment. Among patients with severe renal impairment, the majority received a reduced dose NOAC: apixaban, 91.1%, dabigatran, 80.0%, rivaroxaban, 83.0%.. Between 2011 and 2016, the majority of patients starting NOAC therapy in UK primary care were prescribed a daily dose in line with the approved EU drug label. Underdosing was more than twice as common among patients starting on apixaban than those starting on dabigatran or rivaroxaban. Research into the patient characteristics that may influence inappropriate underdosing of NOACs in UK primary care is warranted.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cross-Sectional Studies; Dabigatran; Female; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban; Stroke; United Kingdom

To determine discontinuation rates, patterns of use and predictors of discontinuation of non-vitamin K antagonist oral anticoagulants (NOACs) among patients with non-valvular atrial fibrillation (NVAF) in the first year of therapy.. Population-based cohort study.. UK primary care.. 11 481 patients with NVAF and a first prescription (index date) for apixaban, dabigatran or rivaroxaban (January 2012 to December 2016) with at least 1 year of follow-up and at least one further NOAC prescription in the year following the index date were identified. 1 year rates and patterns of discontinuation were described.. Outcome measures were the percentage of patients who, in the first year from starting NOAC therapy, discontinued with their oral anticoagulant (OAC) therapy (discontinuation was defined as a gap in OAC therapy of >30 days); switched OAC within 30 days; discontinued and reinitiated OAC therapy. Predictors of discontinuation were also evaluated.. 1 year discontinuation rates according to the index NOAC were 26.1% for apixaban, 40.0% for dabigatran and 29.6% for rivaroxaban. Reinitiation rates were 18.1% for apixaban, 21.7% for dabigatran and 17.3% for rivaroxaban, and switching rates were 2.8% for apixaban, 8.8% for dabigatran and 4.9% for rivaroxaban. More than 93% of reinitiations were with the index NOAC. Patients starting on dabigatran were more likely to switch OAC therapy than those starting on apixaban; ORs 4.28 (95% CI 3.24 to 5.65) for dabigatran and 1.89 (95% CI 1.49 to 2.39) for rivaroxaban. Severely reduced renal function was a predictor of any discontinuation, OR 1.77 (95% CI 1.28 to 2.44).. While the majority of patients with NVAF in the UK initiating NOAC treatment received continuous therapy in the first year of treatment, a substantial proportion of patients experienced gaps in treatment leaving them less protected against thromboembolism during these periods.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cohort Studies; Dabigatran; Female; Humans; Kidney Diseases; Male; Medication Adherence; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban; United Kingdom

To evaluate the safety of phacoemulsification of cataract in patients taking new oral anticoagulants (NOACs).. In a prospective case series, consecutive patients on NOACs (dabigatran, rivaroxaban, or apixaban) who were referred for uncomplicated cataract surgery to the eye institute underwent a thorough ophthalmological and hematological evaluation. Rivaroxaban and apixaban anti-factor Xa tests, and diluted thrombin time for dabigatran, were used for monitoring anticoagulation levels in blood. Blood was drawn for these tests just prior to surgery and at a peak level of the drug at about 4 h post-surgery (2 h after the drug was given). All surgeries were videotaped and patients were examined at 1 and 7 days after the operation. The main outcome measures included assessment of intra-operative, postoperative ocular bleeding, and other related complications.. Thirty-five eyes of 25 unrelated patients ranging in age from 63 to 92 years (mean 77.6 years) underwent phacoemulsification. Intra-operative bleeding was observed in 5 eyes from the conjunctiva or limbus at the main incision site. No intraocular bleeding occurred. No hemorrhagic complications were observed during the 1-week follow-up. According to anti-factor Xa levels prior to surgery and following surgery, 85% of the patients were on therapeutic levels of NOACs.. Clear corneal incision phacoemulsification performed under topical anesthesia can be safely performed in simple cases of cataract without discontinuing NOAC treatment.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antithrombins; Blood Loss, Surgical; Dabigatran; Eye Hemorrhage; Factor Xa Inhibitors; Female; Follow-Up Studies; Humans; Incidence; Israel; Male; Middle Aged; Phacoemulsification; Postoperative Hemorrhage; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban; Thromboembolism

Factor Xa-inhibiting direct oral anticoagulants (FXa-DOACs) undergo hepatic metabolism via cytochrome P-450 (CYP450). Concomitant use of rifampicin, an inducer of these enzymes, with FXa-DOACs, has been shown to decrease FXa-DOAC concentrations in healthy subjects. Several common antiepileptic drugs (AEDs) are known to induce CYP450 enzymes as well. However, little is known regarding the impact of this potential interaction on treatment outcomes with FXa-DOACs.. We analyzed adverse event cases submitted to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from January 2013 to December 2018. We compared the proportion of cases reporting thromboembolic and ischemic adverse events (TAIAEs) with the concomitant use of FXa-DOACs and enzyme-inducing AEDs to the proportion of cases with FXa-DOACs and other AEDs.. During this period, 9693 adverse event cases reported concomitant use of FXa-DOACs and AEDs. Almost all reports (> 99%) involved the use of rivaroxaban or apixaban. Compared with other AEDs, enzyme-inducing AEDs were associated with an 86% increase in the odds of reporting TAIAEs [reporting odds ratio (ROR) 1.86, 95% confidence interval (CI) 1.61-2.15; p < 0.0001]. In secondary separate analyses of rivaroxaban and apixaban, enzyme-inducing AEDs were similarly associated with increased reporting of a TAIAE (ROR 1.79, 95% CI 1.50-2.12, and ROR 1.88, 95% CI 1.41-2.48, respectively).. Using real world data, we observed an increase in the odds of reporting anticoagulation treatment failure among patients treated with FXa-DOACs and concomitant enzyme-inducing AEDs compared to those treated with other AEDs.

Topics: Administration, Oral; Adverse Drug Reaction Reporting Systems; Aged; Anticoagulants; Anticonvulsants; Blood Coagulation; Factor Xa Inhibitors; Female; Humans; Ischemia; Male; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban; United States; United States Food and Drug Administration

Topics: Blood Coagulation Factors; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban

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

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

Vitamin K antagonists (VKA) continue to be the standard of long-term anticoagulation. Direct oral anticoagulants(DOAC) are increasingly used. In many trials DOAC were at least as effective as VKA. In this study we evaluate the bleeding profiles, frequencies and etiologies of patients receiving DOAC versus VKA in a real-life setting. All patients presenting with suspected gastrointestinal bleeding (GIB) in the emergency department of the University Hospital Erlangen in one year were enrolled in this study. They were looked up for the intake of either DOAC (dabigatran, rivaroxaban and apixaban) or VKA. The results showed that 406 patients with suspected GIB were admitted to the emergency unit of the University Hospital Erlangen. In 228 of those patients GIB could be verified (56.2%). Fifty four of those patients (23.7%) were administered either VKA or DOAC. In 35 of those 54 patients (64.8%) GIB was classified as 'major bleeding'. In 27 patients with administration of VKA upper GIB was recorded and lower GIB was detected four times. In 16 patients with administration of DOAC upper GIB was found and lower GIB was found in 7 patients. The presented data do not show higher GIB rates for DOAC (mainly dabigatran and rivaroxaban), but do also not indicate a significantly higher safety of DOAC concerning GIB than VKA. This finding represents a clear contrast to the reduced bleeding rates of DOAC for intracerebral bleeding and other non-GIB events. According to our study, the absolute number of DOAC-associated GIB events is lower than in the VKA group.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Dabigatran; Female; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Vitamin K; Young Adult

Non-vitamin K antagonist oral anticoagulants (NOACs) are a major advance for stroke prevention in atrial fibrillation (AF). Use of the vitamin K antagonist (VKA), warfarin, has dropped 40% since 2010 in our institution. There is limited Irish hospital data on NOAC prescribing for stroke prevention.. Single centre, retrospective observational cohort study of consecutive AF patients at increased risk of stroke and/or awaiting electrical cardioversion. Data on prescribed NOACs from February 2010 till July 2015 was collected from the electronic inpatient record. Appropriateness of prescriptions was based on CHA2DS2-VASC score and accuracy on individual NOAC SPCs. Potential drug interactions and bleeding risk were also quantified.. A total of 348 patients AF and increased risk of stroke (CHA2DS2-VASC score > 1 for men and > 2 for women) were studied. Forty-eight percent were female with a mean age 71 ± 18.6 years, 52% of whom were > 75. Mean CHA2DS2-Vasc and HAS-BLED scores were 4.1 ± 1.8 and 1.4 ± 0.8, respectively. Rivaroxaban, dabigatran and apixaban were prescribed to 154 (54.2%), 106 (34.3%) and 41 (13.2%) patients, respectively. 20.4% had inaccurate prescriptions; 92.9% (n = 65) underdosed and 7.1% (n = 5) on inappropriately higher doses. Neither choice of NOAC, age, history of anaemia, previous bleeding or co-prescribed antiplatelets influenced the accuracy of prescription (p = NS), but decreased renal function appeared to do so (p = 0.05).. Our study highlights significant inaccuracies in NOAC prescribing. Patients commenced on NOACs should be assessed and followed up in a multidisciplinary AF clinic to ensure safe and effective prescribing and stroke prevention.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Humans; Inappropriate Prescribing; Male; Medical Audit; Middle Aged; Prescriptions; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke

The management of stroke risk in patients with non-valvular atrial fibrillation has changed over the past few years. This change has occurred due to the introduction of novel oral anticoagulants (NOACs) such as apixaban, rivaroxaban and dabigatran for the management of non-valvular atrial fibrillation. These agents have shown comparable stroke risk reduction to warfarin in large international multicentre trials [1-3]. This has changed the clinical practice of many treating physicians since their introduction from 2011 to 2013. The purpose of this review was to highlight the now mainstream use of NOAC administration in preference to warfarin, by comparing the trends in the number of prescriptions filled since all three forms of oral anti-coagulant became available in 2013. These agents are being increasingly prescribed due to their ease of use compared to warfarin, which not only requires ongoing monitoring due to narrow therapeutic range but also has many drug and food interactions. Since November 2015, NOACs have become the mainstream choice for anticoagulation in atrial fibrillation likely given their ease of use compared to warfarin. The use of each anticoagulant remains divergent with the use of warfarin continuing to decrease.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Follow-Up Studies; Humans; Incidence; Pyrazoles; Pyridones; Retrospective Studies; Risk Factors; Rivaroxaban; Stroke; Thrombolytic Therapy; Treatment Outcome; Victoria; Warfarin

The International Society of Thrombosis and Haemostasis recommends avoiding direct oral anticoagulants (DOACs) in morbidly obese patients with a body mass index (BMI) >40 kg/m. The objective of this study was to evaluate the efficacy and safety of DOACs in morbidly obese patients with atrial fibrillation or flutter.. A retrospective, single-center cohort study was conducted of patients older than 18 years, with BMI >40 kg/m. A total of 64 patients in each group were included in the study analysis. The incidence rate of ischemic stroke or TIA was 1.75%/year in the DOAC group compared with 2.07%/year in the warfarin group (rate ratio = 0.84; 95% CI = 0.23 to 3.14; P = 0.80). The incidence rate of major bleeding was 2.18%/year in the DOAC group, compared with 4.97%/year in the warfarin group (rate ratio = 0.44; 95% CI = 0.15 to 1.25; P = 0.11). Conclusion and Relevance: Apixaban and rivaroxaban may be considered as alternatives to warfarin for atrial fibrillation or flutter in morbidly obese patients. Dabigatran use in morbidly obese patients needs caution until further studies are conducted.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cohort Studies; Dabigatran; Drug Therapy, Combination; Female; Hemorrhage; Humans; Incidence; Male; Middle Aged; Obesity, Morbid; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Warfarin; Young Adult

Several comparative real-world effectiveness studies on direct oral anticoagulants (DOACs) have been conducted, but an overview of the available evidence remains to be developed, which could provide a better understanding of the value of DOACs relative to vitamin K antagonists (VKAs).. A systematic literature review was conducted on the available real-world evidence (RWE) of three DOACs (rivaroxaban, dabigatran, and apixaban) compared with VKAs (e.g. warfarin), in patients with nonvalvular atrial fibrillation (NVAF).This systematic literature review included RWE published up to December 2016. Studies with > 50 patients reporting on incident and prevalent NVAF cases were included. The following databases were searched: Medline, Embase, and the Cochrane Library. Outcomes of interest included thromboembolic events, all-cause mortality, bleeding events, and nonpersistence. Of the 562 RWE DOACs articles retrieved, 49 presented results for rivaroxaban versus VKAs, 79 for dabigatran versus VKAs, and 18 for apixaban versus VKAs. Substantial heterogeneity was found across patient population, outcome definition, and follow-up period. Major bleeding, ischemic stroke, and intracranial hemorrhage were the most frequent outcomes analyzed.. Overall, the RWE studies were aligned with the Phase 3 trials. However, conflicting results were reported for several outcomes of interest.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Hemorrhage; Humans; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Vitamin K; Warfarin

Steady-state plasma concentrations of anticoagulants and the time since the previous administration in mainly outpatients with atrial fibrillation administered standard or reduced doses were analyzed for 110 elderly Japanese subjects (mean age, 76 years) treated with apixaban (2.5 or 5.0 mg twice daily), dabigatran etexilate (110 or 150 mg twice daily), edoxaban (30 or 60 mg once daily) or rivaroxaban (10 or 15 mg once daily) at one general hospital. The pharmacokinetics in patients treated with standard and reduced doses of the four anticoagulants using liquid chromatography-tandem mass spectrometry was compared with the concentration ranges estimated using physiologically based pharmacokinetic modeling. Reduced doses of anticoagulants resulted in relatively small pharmacokinetic variations compared with the standard dose. Statistical analyses revealed that renal impairment is likely not the sole determinant factor for high plasma concentrations of apixaban, dabigatran, edoxaban and rivaroxaban. Patients with atrial fibrillation should be treated with the correct doses of oral anticoagulants as specified in the package inserts (e.g. reduced doses for elderly patients, patients with low body weights and in combination with P-glycoprotein inhibitor drugs) to avoid excessive or insufficient doses of direct oral anticoagulants.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Dose-Response Relationship, Drug; Female; Humans; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles

Proton pump inhibition (PPI) reduces gastrointestinal bleeding on direct oral anticoagulants. However, PPI may affect dabigatran on-treatment levels; and there is no information regarding the effect of PPI on xabans on-treatment activity. Thus, the aim of this study was to determine the impact of PPI on therapeutic anti-Xa activity in rivaroxaban- and apixaban-treated patients with atrial fibrillation (AF). This single-centre pilot prospective study enrolled 77 consecutive xabans-treated patients (42 rivaroxaban-treated and 35 apixaban-treated patients) with AF. PPI was administrated in 44 patients. Trough and peak anti-Xa activity was assessed with factor Xa-calibrated anti-Xa chromogenic analysis. There were no significant differences in trough anti-Xa activity comparing PPI-treated patients and patients without PPI (80.5 ± 66.5 ng/mL in PPI group vs. 71.6 ± 64.1 ng/mL in non-PPI group, p = 0.57, Table 2). Similarly, there were no significant differences in peak anti-Xa activity between compared groups (175.2 ± 102.5 ng/mL in PPI group vs. 202.9 ± 84.1 ng/mL in non-PPI group, p = 0.21). This pilot study did not reveal significant changes in xabans on-treatment anti-Xa activity according the PPI status.

Topics: Anticoagulants; Atrial Fibrillation; Drug Interactions; Factor Xa Inhibitors; Gastrointestinal Hemorrhage; Humans; Pilot Projects; Prospective Studies; Proton Pump Inhibitors; Pyrazoles; Pyridones; Rivaroxaban

Rapid detection of the anticoagulant effect of oral factor Xa (FXa) inhibitors may be essential in several emergency clinical situations. Specific assays quantifying the drugs are performed in plasma and require a turnaround time that is too long to be useful in emergency situations. Rotational thromboelastometry (ROTEM) is a whole blood coagulation assay of blood viscoelasticity and could be of interest for FXa inhibitor detection in emergency. However, conventional ROTEM reagents only detect high amounts of inhibitors.. The aim of this study was first to assess the effect of whole blood components on the viscoelastic measurement of the effects of FXa inhibitors, and second to evaluate whether a modified ROTEM, triggered with a low amount of tissue factor and a saturating amount of phospholipid vesicles, can reliably detect low levels of FXa inhibitor activity in whole blood.. Diagnostic test study.. A university research laboratory. From November 2014 to April 2016.. Sixty-six patients: 30 treated with rivaroxaban, 17 with apixaban and 19 without treatment.. ROTEM was triggered with 2.5 pmol l of tissue factor and 10 μmol l of phospholipid vesicles.. Modified ROTEM parameters were measured in different experimental conditions: platelet-poor plasma (PPP), platelet-rich plasma, PPP supplemented with fibrinogen and reconstituted whole blood with various haematocrit levels adjusted between 30 and 60%. Modified ROTEM was further validated using whole blood from patients who were either treated or not treated with FXa inhibitors.. Modified ROTEM allowed detection of as little as 25 ng ml FXa inhibitors in PPP, with at least a 1.4-fold increase of the clotting time (P ≤ 0.02). Neither changes of fibrinogen concentration nor variations of platelet count or haematocrit precluded FXa inhibitor detection. A lengthened modified ROTEM clotting time of more than 197 s allowed detection of FXa inhibitor concentrations above 30 ng ml in whole blood with 90% sensitivity and 85% specificity.. Modified ROTEM may be applicable in emergency situations for the detection of FXa inhibitors in whole blood.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Blood Coagulation; Critical Care; Factor Xa Inhibitors; Feasibility Studies; Female; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban; Sensitivity and Specificity; Thrombelastography; Time Factors; Young Adult

Topics: Administration, Oral; Anticoagulants; Antithrombins; Blood Coagulation; Blood Coagulation Tests; Dabigatran; Humans; Platelet Membrane Glycoproteins; Pyrazoles; Pyridones; Rivaroxaban

To describe the characteristics and severity of epistaxis in patients taking factor Xa inhibitors novel anticoagulants.. Retrospective cohort study.. A study of adult patients hospitalized due to spontaneous epistaxis under the treatment of warfarin, rivaroxaban, or apixaban between the years 2011 and 2017 was performed. A control group of patients under antiplatelet therapy (acetylsalicylic acid, clopidogrel) was included. The mean follow-up periods in the warfarin, rivaroxaban, apixaban, and antiplatelet groups were 18, 14.5, 13.5, and 18.2 months, respectively. We compared demographics, location and severity of bleeding, treatment methods, and outcome between the groups.. The study included 109 patients (35 under factor Xa inhibitors), the majority of whom presented with anterior epistaxis (68%). The antiplatelet group had more episodes of epistaxis prior to admission, and required endoscopic surgical control of bleeding more often, in comparison with anticoagulants (2.23 vs. 1.44, P < .05 and 23% vs. 6%, respectively, P < .05). Among anticoagulants, combined therapy (cauterization and packing) was required more frequently in the apixaban group compared to the rivaroxaban and warfarin groups (64% vs. 25% and 33%, respectively, P < .05). The rate of readmissions due to epistaxis, within 1 year of follow-up was lower in the factor Xa inhibitor groups compared with the warfarin and antiplatelet groups (16% vs. 9% and 4%, respectively, P < .05). Cessation of factor Xa inhibitor therapy was effective and uneventful with no further epistaxis events.. Epistaxis under factor Xa inhibitors was effectively treated with no worse and perhaps even a better outcome when compared to other anticlotting medications.. 4 Laryngoscope, 129:119-123, 2019.

Topics: Aged; Anticoagulants; Epistaxis; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Patient Readmission; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Warfarin

The aim of this study was to characterize the risk of a delayed intracranial hemorrhage (ICH) in trauma patients on direct-acting oral anticoagulants (DOACs).. Patients on DOACs admitted to two Level I Trauma Centers between 2014 and 2017 were reviewed. Only patients with a negative admission CT brain were included. The primary outcome was a delayed ICH.. Overall, 249 patients were included. The median age was 81 years with 82% undergoing a repeat CT. Three patients developed a delayed ICH (1.2%). One developed an ICH after receiving tissue plasminogen activator for a cerebrovascular accident after two negative CTs. Excluding this patient, the incidence dropped to 0.8%. None required neurosurgical intervention.. For patients at risk for a TBI who are on DOACs, repeat cross-sectional imaging of the brain when the initial imaging is negative is not necessary. A period of clinical observation may be warranted.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Brain; Brain Injuries, Traumatic; Dabigatran; Female; Humans; Intracranial Hemorrhages; Male; Middle Aged; Neuroimaging; Pyrazoles; Pyridones; Retrospective Studies; Risk; Rivaroxaban; Time Factors; Tomography, X-Ray Computed

Venous thromboembolism (VTE) is a multifactorial disease. Cancer and older age are risk factors for both recurrent VTE and bleeding under anticoagulant therapy. Oral direct factor Xa inhibitors (Xa inhibitors) have been widely used to treat VTE. However, their effectiveness and safety in cancer and elderly patients have not been fully elucidated. A total of 187 consecutive patients who started Xa inhibitors for VTE therapy between September 2014 and September 2016 were recruited. Patients' demographics, changes in VTE amount, VTE recurrence, clinically relevant bleeding, and death until February 2017 were compared between 92 cancer and 95 non-cancer patients, and 57 elderly (≥ 75 years) and 130 non-elderly patients. Compared with non-cancer patients, cancer patients had a significantly higher incidence of deep vein thrombosis (DVT) in the proximal legs, superior vena cava, and upper extremities (p = 0.034), although the patients' demographics and incidence of pulmonary thromboembolism (PE) were similar between the two groups. There were no significant differences in VTE recurrence (p = 0.328) and clinically relevant bleeding (p = 0.078) between the two groups. Death occurred in 29 cancer patients, 23 of whom died of cancer, while there were no deaths among the non-cancer patients. Elderly patients had a lower body weight and creatinine clearance than non-elderly patients. No significant differences between the two groups were found in relation to PE (p = 0.544), DVT site (p = 0.054), recurrent VTE (p = 0.194), clinically relevant bleeding (p = 0.130) and death (p = 0.241). In comparisons among the four groups (elderly and non-elderly patients with and without cancer), recurrent VTE and clinically relevant bleeding were comparable (p = 0.493 and 0.227, respectively), while death was more frequent in cancer patients regardless of age (p < 0.001). The efficacy and safety of Xa inhibitors as VTE treatment were comparable between cancer and non-cancer patients, and in elderly and non-elderly patients. This suggests that Xa inhibitors may be promising drugs for VTE treatment, irrespective of age and comorbid cancer.

Topics: Administration, Oral; Age Factors; Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Female; Follow-Up Studies; Humans; Incidence; Japan; Lower Extremity; Male; Middle Aged; Neoplasms; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Risk Factors; Rivaroxaban; Thiazoles; Treatment Outcome; Venous Thromboembolism

Topics: Aged; Aged, 80 and over; Antidotes; Factor Xa; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Intracranial Hemorrhages; Male; Postoperative Hemorrhage; Practice Guidelines as Topic; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban; Thrombophilia; Thrombosis; Treatment Outcome

Oral anticoagulation (OAC) prescribed to AF patients for the prevention of cardioembolic complications likely has the added benefit of preventing venous thromboembolism (VTE). This study evaluated, among AF patients who are anticoagulated, whether type of OAC was associated with subsequent VTE risk.. Non-valvular AF patients prescribed OACs between 2010 and September 2015 were identified via the MarketScan administrative claims databases. OACs included warfarin and direct OACs (DOACs: dabigatran, rivaroxaban, and apixaban). Incident VTE was defined by ICD-9-CM codes. Patients were matched on age, sex, CHA. In total, 1357 VTE events accrued over a mean follow-up of 484 days. In multivariable-adjusted, propensity score-matched Cox models, relative to new users of warfarin, risk of incident VTE was lower among new users of dabigatran [hazard ratio (95% confidence interval) = 0.55 (0.47-0.66)] and apixaban [0.51 (0.39-0.68)], but similar among new users of rivaroxaban [1.01 (0.87-1.19)]. In head-to-head DOAC comparisons, VTE risk was lower among users of dabigatran [0.48 (0.36-0.64)] and apixaban [0.61 (0.47-0.78)] vs rivaroxaban. Findings were mostly similar across patient sub-groups.. In this large practice-based population of AF patients prescribed OACs for primary prevention of stroke and systemic embolization, subsequent risk of VTE was lowest among those prescribed apixaban and dabigatran, while risk was similar with prescriptions for warfarin and rivaroxaban. Among AF patients prescribed OACs, lowering the risk of VTE may be an additional benefit of apixaban and dabigatran, beyond the reduced bleeding risk observed in randomized clinical trials.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban; Venous Thromboembolism

Direct acting oral anticoagulants (DOACs) are increasingly used for thromboembolic prophylaxis in patients with atrial fibrillation (AF). However, there is limited data to evaluate the use of DOACs for the treatment of pre-existing left atrial appendage thrombus. We aimed to determine the efficacy of DOACs in treatment of left atrial appendage (LAA) thrombus utilizing transesophageal echocardiographic (TEE) and clinical outcomes. In this single-center study, we identified 33 patients that were treated for LAA thrombus with DOAC. Eighteen were treated with apixaban, 10 with dabigatran, and 5 with rivaroxaban. The primary endpoint was defined as resolution of LAA thrombus (in patients undergoing TEE), or death, major bleeding requiring transfusion, intracranial hemorrhage, ischemic stroke, or peripheral embolization. In this study, 15 of the 16 patients treated with DOACs who underwent follow-up TEE had resolution of LAA thrombus, with a mean duration of 112 days. Of the 15 patients who achieved resolution of the LAA thrombus, 14 had resolution by their first follow-up TEE. In the 17 patients without a follow-up TEE, 1 died of a retroperitoneal bleed (28 days after DOAC initiation), and 1 suffered an ischemic stroke (484 days after DOAC initiation). In general, patients without a follow-up TEE were older and had more co-morbidities. Although these results are descriptive and limited in number of patients, we believe this is ample evidence that DOACs are relatively safe and efficacious in treatment of patients with AF and concomitant LAA thrombus.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Appendage; Atrial Fibrillation; Coronary Thrombosis; Dabigatran; Echocardiography, Transesophageal; Female; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Treatment Outcome

Oral anti-Xa inhibitors have demonstrated noninferiority to vitamin K antagonists (VKAs) for the prevention of stroke in patients with atrial fibrillation and recurrent venous thromboembolism. They are associated with a decrease in major bleeding. In contrast with VKA, no coagulation monitoring is required. However, in clinical practice, determination of drug concentration is sometimes necessary.. The objective of this study was to evaluate a low-molecular-weight heparin (LMWH) calibrated anti-Xa assay for the quantification of rivaroxaban and apixaban plasma concentration in emergency.. The anti-Xa plasma concentration of rivaroxaban and apixaban were measured in emergency in 210 patients using STA anti-Xa liquid assay. For each plasma concentration <150 ng/mL of rivaroxaban or apixaban, an anti-Xa assay calibrated with LMWH was performed.

Topics: Aged; Atrial Fibrillation; Blood Coagulation; Blood Coagulation Tests; Calibration; Factor Xa Inhibitors; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Predictive Value of Tests; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Sensitivity and Specificity; Stroke; Venous Thromboembolism

Use of direct-acting oral anticoagulants (DOACs) is increasing, but knowledge about pharmacokinetics and safety in frail patients is lacking.. The aim was to determine serum concentrations and elimination rates of DOACs in older hip fracture patients hospitalized for surgery.. The study included patients ≥ 65 years of age hospitalized for acute hip fracture surgery over a period of 6 months. Use of antithrombotic drugs was registered and serum samples collected for analysis of DOACs (apixaban, dabigatran and rivaroxaban) at admission and surgery. Measured concentrations were assessed in relation to reference (therapeutic) ranges of the respective drugs and applied for half-life calculations. Furthermore, waiting time for surgery was compared between DOAC and warfarin users.. Of 167 patients included (median age 84 years), 11 and 14 used DOACs and warfarin, respectively. Seven of the DOAC-treated patients had concentrations above the upper reference range (> 300 nM) at admission, and concentrations were still in the reference range for five of these at surgery. Elimination half-lives could be estimated in eight patients and ranged between 14.6 and 59.7 h (median 21.6). The observed waiting time for surgery was longer for patients using DOACs than warfarin (median 44 vs. 25 h).. This pilot study indicates that older patients prone to hip fracture are at risk of being exposed to therapeutic serum concentrations of DOACs during surgery due to reduced drug elimination rates. The observation that almost 50% of the patients had therapeutic concentrations at surgery should be investigated further regarding safety of DOAC use in this frail elderly population.

Topics: Aged; Aged, 80 and over; Anticoagulants; Dabigatran; Female; Hip Fractures; Humans; Male; Pilot Projects; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban; Warfarin

There is limited clinical experience with the use of coagulation concentrates to reverse the effect of direct oral anticoagulants. We assess the achievement of effective clinical hemostasis with the use of 4-factor prothrombin complex concentrate (PCC) in patients on apixaban or rivaroxaban presenting with major bleeding. A retrospective chart review was conducted at a tertiary referral medical center in the USA. We assess the achievement of clinical hemostasis using 4-factor PCC in patients on chronic apixaban or rivaroxaban therapy presenting with major bleeding. Clinical hemostasis was assessed by the International Society of Thrombosis and Hemostasis Scientific and Standardization Subcommittee criteria. A total of 29 patients are included in the study. The most common site of bleeding was intracranial hemorrhage (ICH) (72.4%), followed by gastrointestinal bleed (13.8%). Clinical hemostasis was achieved in 21 (72.4%) patients. Patients who did not achieve clinical hemostasis (27.6%) suffered from ICH, and all of them died during hospitalization except for two patients who were discharged with neurologic deterioration. One patient developed multiple brain infarctions after receiving 4-factor PCC. Sixteen patients (55.2%) were receiving concomitant medications that interact with apixaban and rivaroxaban and increase the risk of bleeding. Four-factor PCC appears to be effective in achieving clinical hemostasis in patients on apixaban or rivaroxaban presenting with major bleeding. It may be an alternative to patients who need anticoagulation reversal if the specific antidote, andexanet alfa, is not available.

Topics: Aged; Aged, 80 and over; Alabama; Blood Coagulation; Blood Coagulation Factors; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Treatment Outcome

The aim of this study was to compare the clinical effectiveness and safety of direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) in routine clinical practice.. This retrospective cohort study used linked administrative data. The study population (n = 14 577) included patients with a diagnosis of AF (confirmed in hospital) who initiated DOAC treatment in Scotland between August 2011 and December 2015. Multivariate Cox proportional hazard models were used to estimate hazard ratios of thromboembolic events, mortality and bleeding events.. No differences between the DOACs were observed with regard to the risk of stroke, systemic embolism or cardiovascular death. In contrast, the risk of myocardial infarction was higher among patients prescribed apixaban in comparison to those on rivaroxaban (HR 1.67, 95% CI 1.02-2.71), and all-cause mortality was higher among rivaroxaban patients in contrast to both apixaban (1.22 [1.01-1.47]) and dabigatran (1.55 [1.16-2.05]) patients; rivaroxaban patients also had a higher risk of pulmonary embolism than apixaban patients (5.27 [1.79-15.53]). The risk of other major bleeds was higher among rivaroxaban patients compared to apixaban (1.50 [1.10-2.03]) and dabigatran (1.58 [1.01-2.48]) patients; the risks of gastrointestinal bleeds and overall bleeding were higher among rivaroxaban patients than among apixaban patients (1.48 [1.01-2.16] and 1.52 [1.21-1.92], respectively).. All DOACs were similarly effective in preventing strokes and systemic embolisms, while patients being treated with rivaroxaban exhibited the highest bleeding risks. Observed differences in the risks of all-cause mortality, myocardial infarction and pulmonary embolism warrant further research.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Pulmonary Embolism; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Scotland; Stroke; Treatment Outcome

This study examined potential differences in bleeding between apixaban and rivaroxaban, the most commonly utilized direct oral anticoagulants at the Richard L. Roudebush VA Medical Center. Additionally, the analysis included a comparison between observed and literature-reported bleeding rates. This retrospective chart review examined 452 (39%) Veterans receiving rivaroxaban and 716 (61%) Veterans receiving apixaban. Bleeding rates were expressed per 100 patient-years and the overall rates were analyzed as the primary analysis. Secondary objectives included comparisons based on indication and severity, as well as comparisons to literature-reported bleed rates, time to bleeding event, and location of the bleed. The analysis did not detect any statistically significant differences between apixaban and rivaroxaban in terms of overall, (ARR 0.90% per 100 patient-years, 95% CI - 0.58 to 2.38%, p > 0.05) major, (ARR 0.22% per 100 patient-years, 95% CI - 0.74 to 1.17%, p > 0.05) or non-major clinically relevant (ARR 0.35% per 100 patient-years, 95% CI - 0.57 to 1.27%, p > 0.05) bleeding. Observed bleeding for both rivaroxaban and apixaban in the Veteran population exceeded the rates reported by the literature when used for atrial fibrillation (1.96% vs. 0.15%, p < 0.05; 1.08% vs. 0.16%, p < 0.05) but the opposite was seen for long term venous thromboembolism (VTE) treatment (3.97% vs. 8.03%, p < 0.0001; 0.14% vs. 15.51%, p < 0.0001) or extended VTE prophylaxis (0.07% vs 5.98%, p < 0.0001; 0.07% vs 1.88%, p < 0.01). Results from this study suggest these agents impart similar levels of risk, but variations in bleeding risk between the Veteran population and the patients in the original clinical trials may exist.

Topics: Administration, Oral; Aged; Aged, 80 and over; Atrial Fibrillation; Blood Coagulation; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Risk Assessment; Risk Factors; Rivaroxaban; Time Factors; Treatment Outcome; United States; United States Department of Veterans Affairs; Venous Thromboembolism; Veterans Health

Direct oral anticoagulants (DOACs) require no laboratory monitoring, but they interfere with almost all clotting tests to a varying degree, depending on the DOAC, assay principles and reagents used. DOAC Stop (Haematex Research, Sydney, Australia) has recently been shown to adsorb DOACs from spiked and patient plasmas. The aim of our work was to investigate the DOAC Stop effect on a range of haemostasis assays on plasmas collected from patients on rivaroxaban or apixaban, to see whether it removes the effect of these drugs to enable more accurate interpretation of coagulation assays.. Samples from patients anticoagulated with either rivaroxaban, apixaban or no anticoagulant were tested for prothrombin time (PT), activated partial thromboplastin time (APTT), DOAC-specific anti-Xa assay, factor VIII (one-stage and chromogenic assay) and DRVVT (low and high phospholipid) before and after sample treatment with DOAC-Stop.. DOAC Stop significantly removed the effects of rivaroxaban and apixaban on PT, APTT, anti-Xa activity, factor VIII (one-stage and chromogenic assays), and DRVVT (low and high phospholipid reagents), and reduced the number of false positive of lupus anticoagulant interpretations in patients on rivaroxaban. There was no effect on the results from patients that were not anticoagulated.. This small study suggests that it is likely that DOAC Stop can be used in laboratories to screen for coagulopathy or lupus anticoagulants in samples containing rivaroxaban or apixaban. Care should be taken in the interpretation of results since complete reversal of the anti-Xa effect did not occur in every sample.

Topics: Administration, Oral; Anticoagulants; Blood Coagulation Tests; Female; Humans; Male; Pyrazoles; Pyridones; Rivaroxaban

Management of acute, major or life threatening bleeding in the presence of direct acting oral anticoagulants (DOAC) is unclear. In the absence of a specific antidote, or in situations where there is a need for adjunctive therapy, the ideal prothrombin complex concentrate and dose is unclear. The goal of our study was to evaluate the outcomes of our reduced dosing strategy with FEIBA in patients experiencing a DOAC-related bleeding event.. Retrospective analysis of patients treated with FEIBA for a DOAC-related bleeding event.. Academic medical center PATIENTS: Consecutive patients between May 2011 and April 2017 receiving FEIBA for a DOAC-related bleed INTERVENTIONS: None MEASUREMENTS & MAIN RESULTS: Of the 64 patients included in this analysis, 38 patients received low dose FEIBA (mean 10.0 ± 3.6 units/kg) and 26 received moderate dose (mean 24.3 ± 2.1 units/kg) FEIBA; an additional dose was requested in 6 patients. Six dabigatran patients received idarucizumab. 30 day event rates included 5 thromboembolic events (8%) and 9 (14%) patients expired. Follow-up CT-imaging for ICH, endoscopy/colonoscopy, or interventional radiology exams did not reveal any clinically concerning active bleeding or hematoma expansion except in 2 ICH patients with slight expansion between imaging sessions.. Low (<20 units/kg) to moderate (20-30 units/kg) doses of FEIBA, with the option for a repeat dose, may be an effective management strategy for obtaining hemostasis in DOAC-related major bleeding events.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation Factors; Coagulants; Dabigatran; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Treatment Outcome; Young Adult

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Brain; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Venous Thrombosis

Continuous usage of direct oral anticoagulants (DOACs) among nonvalvular atrial fibrillation (NVAF) patients is essential to maintain stroke prevention. We examined switching and discontinuation rates for the three most frequently initiated DOACs in NVAF patients in the USA.. Patients who initiated apixaban, rivaroxaban, or dabigatran (index event/date) were identified from the Pharmetrics Plus claims database (Jan 1, 2013-Sep 30, 2016, includes patients with commercial and Medicare coverage) and grouped into cohorts by index DOAC. Patients were required to have a diagnosis of NVAF and continuous health plan enrollment for 12 months prior to the index date (baseline period) and at least 3 months during the follow-up period. Drug switching rates to any other DOAC or warfarin and index DOAC discontinuation rate were evaluated separately with descriptive statistics, Kaplan-Meier analysis, and multivariable Cox regression analysis.. Of the NVAF study population (n = 41,864), 37% initiated apixaban (n = 15,352; mean age 62 years), 51% initiated rivaroxaban (n = 21,250; mean age 61 years), and 13% initiated dabigatran (n = 5262; mean age 61 years). During the follow-up period, the unadjusted drug switching rates of patients treated with apixaban, rivaroxaban, and dabigatran were 3.6%, 6.3%, and 11.1%, respectively (p < 0.001 across the three cohorts); while the index DOAC discontinuation rates were 52.8%, 60.3%, and 62.9%, respectively (p < 0.001). After we controlled for differences in patient characteristics, patients treated with rivaroxaban (HR 1.8; 95% CI 1.6-2.0; p < 0.001) and dabigatran (HR 3.4; 95% CI 3.0-3.8, p < 0.001) had a significantly greater likelihood for drug switching than patients treated with apixaban. Also, both rivaroxaban (HR 1.1; 95% CI 1.1-1.2, p < 0.001) and dabigatran (HR 1.3; 95% CI 1.2-1.3, p < 0.001) treated patients were more likely to discontinue treatment.. In the real-world setting, patients with NVAF newly treated with apixaban were less likely to switch or discontinue treatment compared to patients treated with rivaroxaban or dabigatran.. Pfizer and Bristol-Myers Squibb.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Treatment Adherence and Compliance; United States; Warfarin

We used the US Department of Defense Military Health System database to compare the safety and effectiveness of direct oral anticoagulants (DOACs) in patients with non-valvular atrial fibrillation (NVAF) initiating dabigatran vs. rivaroxaban or apixaban.. Two cohorts of adults with NVAF, newly initiated on standard-dose DOAC, were identified based on clinical approval dates: July 2011-June 2016 for dabigatran (150 mg b.i.d.) or rivaroxaban (20 mg QD) and January 2013-June 2016 for dabigatran (150 mg b.i.d.) or apixaban (5 mg b.i.d.). Propensity score matching (1:1) identified two well-balanced cohorts (dabigatran vs. rivaroxaban n = 12 763 per treatment group; dabigatran vs. apixaban n = 4802 per treatment group). In both cohorts, baseline characteristics and follow-up duration were similar between treatment groups. Patients newly initiating dabigatran had significantly lower risk of major bleeding vs. rivaroxaban [2.08% vs. 2.53%; hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.70-0.97; P = 0.018], while stroke risk was similar (0.60% vs. 0.78%; HR 0.77, 95% CI 0.57-1.04; P = 0.084). The dabigatran vs. apixaban cohort analysis found no differences in risk of major bleeding (1.60% vs. 1.21%; HR 1.37, 95% CI 0.97-1.94; P = 0.070) or stroke (0.44% vs. 0.35%; HR 1.26, 95% CI 0.66-2.39; P = 0.489).. Among NVAF patients newly initiated on standard-dose DOAC therapy in this study, dabigatran was associated with significantly lower major bleeding risk vs. rivaroxaban, and no significant difference in stroke risk. For dabigatran vs. apixaban, the reduced sample size limited the ability to draw definitive conclusions.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antithrombins; Atrial Fibrillation; Comparative Effectiveness Research; Dabigatran; Databases, Factual; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Military Medicine; Pyrazoles; Pyridones; Retrospective Studies; Risk Factors; Rivaroxaban; Stroke; Time Factors; Treatment Outcome; United States; United States Department of Defense; Young Adult

To compare the occurrence of haemorrhages among the different oral anticoagulants (OAC) and to analyse factors that influence it.. Single-centre, observational, retrospective study. After studying the total population treated with OAC, patients who were treated with an OAC from July 2015 to December 2015 in the II Sector of the Zaragoza Hospital, who consulted the Emergency Department of the Miguel Servet University Hospital and presented a haemorrhagic event, were analysed. Patients' demographic data, clinical variables and data on the haemorrhagic event characteristics were gathered.. There were 9,452 patients treated with an OAC, 371 (3.9%) of which presented a haemorrhagic event. The frequency per OAC was; 4.1% (311) in patients treated with vitamin K antagonists, 3.8% (33) with rivaroxaban, 3.3% (19) with dabigatran and 2.1% (8) with apixaban. In the multivariate analysis, only the choice of anticoagulant and sex had a statistically significant influence of a lower risk of haemorrhage, in particular the dose of apixaban at 2.5mg and being female. (OR=0.1, CI=0.014-0.71 and OR=0.688, CI=0.55-0.85, respectively).. According to the results obtained, females and patients undergoing treatment with apixaban presented lower haemorrhagic risk, although there are doubts about whether this better safety profile is related to underdosing, which could influence its effectiveness. Therefore, these results should be analysed with caution and further studies are needed to confirm this data.

Topics: Administration, Oral; Age Factors; Aged; Aged, 80 and over; Antithrombins; Female; Hemorrhage; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Risk Factors; Rivaroxaban; Sex Factors; Spain

Direct oral anticoagulants (DOACs) have become the standard for thromboembolic risk management. In cases of major bleeding, trauma, or urgent surgery, accurate monitoring of DOAC activity is desirable; however, there is often no rapid, readily available test. We therefore explored the degree to which DOAC activity correlated with two coagulation assays: rotational thromboelastometry (ROTEM) and a standard coagulation assay in bleeding patients. We conducted a retrospective review of patients who experienced bleeding while on DOAC therapy from 2015 to 2017 at a Level 1 trauma center. ROTEM (EXTEM-clotting time {CT} in seconds), activated partial thromboplastin time (aPTT) (in seconds), prothrombin time (PT) (in seconds), DOAC specific drug test (anti-Xa and Hemoclot in ng/mL), and relevant clinical parameters were recorded. Descriptive statistics (median, range) and Spearman correlation coefficients were estimated. Differences between correlations were tested using Williams' t test. Twelve cases were reviewed (13 separate bleeding episodes). Sixteen measurements of DOAC activity, EXTEM-CT, and PT were obtained. The correlations with rivaroxaban activity were 0.96 and 0.86 (p = 0.2062) for PT and EXTEM-CT, respectively. The correlations with apixaban activity were 0.63 and 0.56 (p = 0.7175) for PT and EXTEM-CT, respectively. Analyses were not conducted for dabigatran due to limited data. Although not statistically significant, PT appears to have a higher correlation with direct Xa inhibitor activity than EXTEM-CT. Further research with larger samples is necessary to clarify the differences between ROTEM and standard assays in detecting DOAC activity.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Blood Coagulation; Dabigatran; Drug Monitoring; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Partial Thromboplastin Time; Predictive Value of Tests; Prothrombin Time; Pyrazoles; Pyridones; Reproducibility of Results; Retrospective Studies; Rivaroxaban; Thrombelastography; Treatment Outcome

This retrospective study investigated the efficacy and safety of prothrombin complex concentrates (PCCs) for management of major bleeding events (MBE) in 344 patients receiving the anticoagulants rivaroxaban, apixaban or warfarin during the period January 2016 to April 2018. Median (range) PCC dose was 2000 units (1000-4500). Intracranial haemorrhage (ICH) was the most common indication (137/344, 39·8%) for PCC use followed by gastrointestinal bleeding (93/344, 27%). ICH patients more frequently received rivaroxaban (62·5%) or apixaban (52·5%) compared to warfarin (34·5%), P = 0·002; and visceral bleeding patients received warfarin more frequently (24·2%) than rivaroxaban (5%) or apixaban (10%), P = 0·003. Median rivaroxaban and apixaban levels were 230 ng/ml (47-759) and 159 ng/ml (45-255). Median International Normalised Ratio pre- and post-PCC in patients on warfarin were 3·4 (1·9-15·4) and 1·2 (1·0-1·9). Blood products use was the same between groups. Thirty-day mortality and re-bleeding rates in patients with ICH were 35% (P = 0·50) and 18% (P = 0·90) with no differences between the groups. Thrombosis occurred in 4·1% patients within 30 days with no difference between groups. Two of 91 (2·2%) patients with ICH only (both on warfarin) had ischaemic strokes within 30 days post-PCC. In conclusion, there was no difference in the safety (thrombosis) or efficacy (30-day mortality, re-bleeding) in use of PCC for MBE in patients on warfarin, rivaroxaban or apixaban.

Topics: Aged; Aged, 80 and over; Blood Coagulation Factors; Disease-Free Survival; Female; Gastrointestinal Hemorrhage; Humans; Intracranial Hemorrhages; Male; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban; Survival Rate; Warfarin

Topics: Anticoagulants; Humans; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Venous Thromboembolism

Apixaban and rivaroxaban, both direct-acting oral anticoagulants, are being increasingly used in routine clinical practice because of their fixed dosing and favourable pharmacological profiles. Differences in the risk of recurrent venous thromboembolism and major bleeding events between the two drugs are currently unknown. We aimed to compare the effectiveness and safety of apixaban and rivaroxaban in prevention of recurrent venous thromboembolism and major bleeding events in patients with venous thromboembolism.. We did a retrospective cohort analysis of data from the Truven Health MarketScan commercial and Medicare Supplement claims databases in the USA. We analysed data for adult patients with newly diagnosed venous thromboembolism (deep vein thrombosis or pulmonary embolism) who were new users of apixaban or rivaroxaban between Jan 1, 2014, and Dec 31, 2016. Patients who did not initiate the study drugs within 30 days of their diagnosis, those without 12 months of continuous enrolment in medical and pharmacy benefits, and those who used other anticoagulants during the baseline period were excluded. The primary effectiveness outcome was the incidence of recurrent venous thromboembolism and the primary safety outcome was the incidence of major bleeding events. Cox-proportional hazard models after propensity score matching were used to calculate the hazard ratio (HR) and 95% CI.. After propensity score matching, 15 254 patients were included in the cohort (3091 apixaban users and 12 163 rivaroxaban users). The crude incidence of recurrent venous thromboembolism was three per 100 person-years in the apixaban group and seven per 100 person-years in the rivaroxaban group. The incidence of major bleeding was three per 100 person-years in the apixaban group and six per 100 person-years in the rivaroxaban group. In multivariable Cox regression models, the use of apixaban compared with rivaroxaban was associated with decreased risk of recurrent venous thromboembolism (HR 0·37 [95% CI 0·24-0·55]; p<0·0001) and major bleeding events (0·54 [0·37-0·82]; p=0·0031).. Based on our findings, apixaban seems to be more effective than rivaroxaban in preventing the development of recurrent venous thromboembolism and major bleeding events. Our data might give some assurance to clinicians that apixaban can be an effective and safe therapeutic option for treatment of patients with venous thromboembolism.. None.

Topics: Anticoagulants; Cohort Studies; Female; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Venous Thromboembolism

The correlation between direct oral anticoagulants (DOACs) or Vitamin K Antagonist (VKAs) intake and the incidence of intracranial complications after minor head injury (MHI) is still object of debate: preliminary observation seems to demonstrate lower incidence in intracranial bleeding complications (ICH) in patients taking DOACs than VKA. METHODS. This prospective and observational study was performed to clarify the incidence of ICH in patients in DOACs compared to VKAs. Between January 2016 and April 2018 we have recorded in our ED patients with MHI taking oral anticoagulants. Their hemorragic risk score was calculated and recorded for each patient (Has Bled, Atria and Orbit). RESULTS A total of 402 patients with MHI taking anticoagulant were collected: 226 were receiving one of the four DOACs (dabigatran, rivaroxaban, apixaban or edoxaban) while 176 patients were in therapy with VKA. The rate of intracranial complications was significantly lower in patients receiving DOACs than in patients treated with VKA (p < 0.01). In the VKA group two patients died because of intracranial bleeding. No deaths were recorded in the DOACs group. DISCUSSION patients with MHI who take DOACs have a significant lower incidence of intracranial bleeding complications than those treated with vitamin k antagonists. This statement is supported by the observation that the hemorrhagic risk, measured according to the chosen scores, was similar between the two groups.

Topics: Aged; Aged, 80 and over; Anticoagulants; Craniocerebral Trauma; Dabigatran; Female; Humans; Intracranial Hemorrhages; Male; Middle Aged; Pyrazoles; Pyridines; Pyridones; Risk; Rivaroxaban; Thiazoles; Vitamin K; Warfarin

Non-valvular atrial fibrillation patients receiving non-vitamin K antagonist oral anticoagulants (NOACs) have half the incidence of intracerebral hemorrhage (ICH) compared to those receiving warfarin. However, the differences in outcomes of NOAC-associated ICH (NICH) and warfarin-associated ICH (WICH) remain controversial. In this study, we investigated the clinical outcome and radiologic findings of ICH in Asian patients receiving NOACs or warfarin. We retrospectively reviewed the medical records of 544 ICH patients admitted to our hospital from January 2013 through December 2017, and compared the baseline demographics, clinical characteristics, ICH-related radiologic findings, and clinical outcome between the WICH and NICH groups. WICH and NICH were diagnosed in 46 and 13 patients, respectively. Lesions were located more frequently in the supratentorial deep area (45.7% and 46.2%) than the lobar area (30.4% and 30.8%) or brainstem and cerebellum (23.9% and 23.1%) in the WICH and NICH groups, respectively. The hematoma expansion and concomitant intraventricular hemorrhage (IVH) rate was significantly higher in the WICH group than in the NICH group (58.7% versus 7.7%, P = 0.001 and 50.0% versus 15.4%, P = 0.030, respectively). Hematoma expansion (odds ratio [OR]: 50.546; 95% confidence interval [CI]: 2.763-924.748; P = 0.008) and concomitant IVH (OR: 9.240; 95% CI: 1.450-58.892; P = 0.019) were independently associated with mortality at three months, after adjustment for confounding variables. Our results indicate that the radiological findings and clinical outcome at three months in patients with ICH are more favorable in those receiving NOAC therapy than in those receiving warfarin treatment.

Topics: Administration, Oral; Aged; Anticoagulants; Asian People; Atrial Fibrillation; Cerebral Hemorrhage; Dabigatran; Female; Humans; Male; Middle Aged; Odds Ratio; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Warfarin; Young Adult

Topics: Humans; Pyrazoles; Pyridones; Rivaroxaban; Venous Thrombosis

There are no clear and consistent guidelines on how to utilize DOAC assays, and reports on the use of DOAC levels in clinical practice is limited. The objective of this study was to analyze why DOAC levels are ordered, how the results affect clinical decision-making, and to determine if DOAC assays are utilized appropriately. This was a retrospective chart review study analyzing 150 dabigatran, rivaroxaban, and apixaban levels performed at a single institution. The majority of DOAC assays were ordered in situations or special patient populations where confirming absence or detecting presence of drug may be useful. The most common indication for ordering assays was prior to an invasive procedure. Most DOAC levels were timed appropriately but peak levels were most likely to be incorrectly ordered. Clinical decisions following level results depended on indication for ordering and were most commonly used to determine whether or not to proceed with an invasive procedure. The results of our study suggest while DOAC assays are generally ordered for useful indications, there is still a lack of understanding of when levels should be drawn and how to interpret DOAC assay results.

Topics: Anticoagulants; Dabigatran; Decision Making; Drug Monitoring; Factor Xa Inhibitors; Female; Humans; Male; Practice Patterns, Physicians'; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Surgical Procedures, Operative

To assess the impact of the introduction of direct oral anticoagulants upon the outcomes from elective electrical cardioversion for atrial fibrillation.. This is a retrospective comparison of delay to elective cardioversion with different anticoagulants. The data was gathered from a large regional hospital from January 2013 to September 2017. There were 3 measured outcomes: 1) the time in weeks from referral to the date of attempted electrical cardioversion; 2) the proportion of patients who were successfully cardioverted; and 3) the proportion of patients who remained in sinus rhythm by the 12 week follow-up. Time-to-cardioversion was non-parametrically distributed so was analysed with Kruskal-Wallis testing and Mann-Whitney-U testing. Maintenance of sinus rhythm was analysed using z-testing.. 1,374 patients were submitted to cardioversion. The referrals for cardioversion were either from primary care or from cardiologists. At the time of cardioversion, 789 cases were anticoagulated on warfarin (W), 215 on apixaban (A) and 370 on rivaroxaban (R). All 3 cohorts were initially compared independently using Kruskal-Wallis testing. This demonstrated a significant difference in the delay (measured in weeks) between the A and W group (A = 7, W = 9, P<0.00001); the R and W group (R = 7, W = 9, P<0.00001) and no difference between R and A (A = 7, R = 7, P = 0.92). As there was no difference between the A and R groups, they were combined to form the AR group. The AR group was compared to the W group using Mann-Whitney-U testing which demonstrated a significant delay between the groups (AR = 7, W = 9, P<0.00001). Excluding patients with prior or unknown attempts of cardioversion (n = 791), the W patients (n = 152) were less successful in achieving sinus rhythm at cardioversion than the AR (n = 431) group (W = 95% vs AR = 99% P = 0.04). However at 12 weeks, incidence of sinus rhythm was significantly different (W = 40% vs AR = 49% P = 0.049). These groups were compared by z testing. At 12 weeks' follow-up there was no statistical difference in rate of adverse consequences between the AR group and the W group, but the rate of adverse consequences was too low to draw further conclusions.. DOACs appear to significantly shorten the latency between the decision to cardiovert and the cardioversion procedure by at least 2 weeks compared to warfarin in a real-world setting. In this study, patients who had not previously been cardioverted who were anticoagulated with warfarin had a significantly lower probability of conversion to sinus rhythm and a significantly lower probability to remain in sinus rhythm at the 12 week follow-up compared to the combined apixaban and rivaroxaban group.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Atrial Flutter; Clinical Decision-Making; Electric Countershock; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Thromboembolism; Time-to-Treatment; Treatment Outcome; Warfarin

It is not known whether direct-acting oral anticoagulants (DOACs), such as dabigatran, apixaban, and rivaroxaban increase the risk of bleeding complications during or after coronary catheterization. The aim of this study was to investigate the safety of uninterrupted DOAC treatment during diagnostic radial coronary angiography (CAG).. This study included 160 patients who underwent diagnostic radial cardiac catheterization. The 60 patients in the group who were using a DOAC (apixaban, rivaroxaban, or dabigatran) were enrolled in a Group A. Post-procedure results from patients in Group A were compared with those of an age- and sex-matched control group (Group B) that included 100 patients who underwent radial CAG who did not use a DOAC.. There was no significant difference in the procedure and compression times, creatinine level, or presence of hypertension, diabetes mellitus, smoking, alcohol use, vascular disease, or congestive heart failure between the 2 groups. During the 1 -month follow-up period, only 1 radial occlusion was registered in the control group (Group B). There was no case of a large hematoma (>5 cm or extending to the forearm), dissection, fistula, perforation, or compartment syndrome. Hematomas smaller than 5 cm were seen in 2 patients (1 in each group). No thrombotic events were observed during follow-up examinations.. Performing radial CAG with uninterrupted DOAC treatment appears to carry no risk of increased early or short-term complications. The simple, uninterrupted DOAC strategy is comfortable, easy, and safe.

Topics: Aged; Anticoagulants; Cardiac Catheterization; Coronary Angiography; Dabigatran; Female; Hematoma; Humans; Male; Middle Aged; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban; Thrombosis

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Humans; Italy; Male; Propensity Score; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban; Stroke

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

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

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

In the past decade, direct-acting oral anticoagulants (DOAC) have been introduced to medical practice for several indications, with a wide range of dosing regimens. As both over- and under-dosing might lead to life-threatening events, development of methods promoting safe and effective utilization of these agents is imperative. The Hadassah Clinical Pharmacy team initiated a hospital-wide program, for monitoring and promoting safe and effective prescription of DOAC during hospitalization. This study describes the types of drug related problems addressed and the program's performance in terms of consultation rates and physician acceptance.. Electronic medical records throughout the hospital were screened for DOAC orders. All DOAC orders were assessed by a clinical pharmacist for potentially-inappropriate prescribing. When potentially-inappropriate prescribing or a drug-related problem was identified, the clinical pharmacist provided consultation on management options. In specific cases, additional guidance was provided by coagulation and pharmacology specialists. Data on patient characteristics, clinical pharmacist consultations, and physician response was retrospectively retrieved for the first six months of 2017. Characteristics of patients with and without consultations were compared, consultations were categorized by the recommended management of the drug related problem, and physician acceptance rates were evaluated by category.. During the evaluated period, 585 patients with DOAC orders were identified. Patients were evenly distributed by gender, and age averaged 78 years. Most patients received apixaban (75%) followed by rivaroxaban (14%) and dabigatran (11%), and most (63%) received "reduced dose" regimens. Clinical pharmacists provided 258 consultations for 210 patients, regarding anticoagulation management, such that more than one in three patients on DOAC had potentially inappropriate prescribing or drug related problems. Consultations included alerts regarding potentially inappropriate DOAC doses and recommendations to increase (29%) or decrease (5%) the dose, potentially inappropriate concomitant antiplatelet agents (20%), need for DOAC level monitoring (23%), and alerts regarding other drug related problems (23%). More than 70% of recommendations were accepted by the attending physician.. Due to the complexity of DOAC management, potentially-inappropriate prescribing and drug related problems are common. Multidisciplinary collaborative projects including review and consultation by clinical pharmacists are an effective method of improving management of patients on DOAC.. Retrospectively registered at clinicaltrials.gov, NCT03527615 .

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Dabigatran; Drug Utilization Review; Female; Humans; Israel; Male; Medical Overuse; Pharmacists; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban

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

Patients taking oral anticoagulants (OACs) currently represent one-third of all patients treated for epistaxis and an upward trend is expected. New direct oral anticoagulants (DOACs) have been on the market for approximately 10 years. DOACs are favoured over Vitamin K-Antagonists (VKAs) in the current guidelines. There are barely studies that investigate the impact of DOACs on patients with epistaxis. A retrospective study was performed analysing all patients who had stationary treatment for epistaxis from 01.01.2011 to 01.01.2018 in a tertiary care centre. In a total of 466 patients, 46.1% were on OACs. The main indication was atrial fibrillation (AF, 67.4%).The number of DOACs taken surpassed that of the VKAs during the past 2 years. The length of hospital stay was significantly longer in the phenprocoumon group (3 ± 0.2 days) in comparison to both the rivaroxaban (2.3 ± 0.1) and the apixaban (2.2 ± 0.1) groups (p = 0.005). Posterior epistaxis occurred more frequently in the phenprocoumon group (10.8%) than in the rivaroxaban (0%) and apixaban (0%) groups (p = 0.03). A correlation between CHA

Topics: Aged; Anticoagulants; Atrial Fibrillation; Epistaxis; Factor Xa Inhibitors; Female; Humans; Length of Stay; Male; Middle Aged; Phenprocoumon; Pyrazoles; Pyridones; Retrospective Studies; Risk Assessment; Rivaroxaban

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

To compare the clinical efficacy and safety of apixaban with those of rivaroxaban for the treatment of acute venous thromboembolism (VTE).. Consecutive patients enrolled in the Mayo Thrombophilia Clinic Registry (between March 1, 2013, and January 30, 2018) and treated with apixaban or rivaroxaban for acute VTE were followed forward in time. The primary efficacy outcome was VTE recurrence. The primary safety outcome was major bleeding; the second safety outcome was clinically relevant nonmajor bleeding (CRNMB); and the third was a composite of major bleeding or CRNMB.. Within the group of 1696 patients with VTE enrolled, 600 (38%) were treated either with apixaban (n=302, 50%) or rivaroxaban (n=298, 50%) within the first 14 days of VTE diagnosis and who completed at least 3 months of therapy or had a study event. Recurrent VTE was diagnosed in 7 patients (2.3%) treated with apixaban and in 6 (2%) treated with rivaroxaban (adjusted hazard ratio [aHR], 1.4; 95% CI, 0.5-3.8). Major bleeding occurred in 11 patients (3.6%) receiving apixaban and in 9 patients (3.0%) receiving rivaroxaban (aHR, 1.2; 95% CI, 0.5-3.2). Clinically relevant nonmajor bleeding was diagnosed in 7 patients (2.3%) receiving apixaban and in 20 (6.7%) receiving rivaroxaban (aHR, 0.4; 95% CI, 0.2-0.9). The rates of composite major bleeding or CRNMB were similar (aHR, 0.6; 95% CI, 0.3-1.2). Most study events occurred in patients with cancer.. In the setting of a standardized, guideline-directed, patient-oriented clinical practice, the efficacy and safety of apixaban and rivaroxaban for the treatment of acute VTE were comparable.

Topics: Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Recurrence; Rivaroxaban; Treatment Outcome; Venous Thromboembolism

Background Direct oral anticoagulants (DOACs) cause false positive lupus anticoagulant (LA) results. We assessed the impact of DOAC-Stop, reversing in vitro effects of DOACs, on LA testing in anticoagulated patients. Methods We assessed 75 venous thromboembolism patients aged 44.5±14.6 years. Blood samples were collected 2-28 h since intake of DOACs, including 50 patients on rivaroxaban, 20 on dabigatran and five on apixaban. LA testing was performed at baseline and after DOAC-Stop treatment. Positive LA was defined as the normalized (patient/standard plasma clotting time) LA screening and screening (LA1)/confirmation (LA2) ratios exceeding 1.2. Results LA diluted Russell's viper venom time (dRVVT) normalized screening test revealed abnormal results in 73 (97.3%) and activated partial thromboplastin time (APTT)-LA in 49 (65.3%) patients. In six (8%) patients, antiphospholipid syndrome (APS) was diagnosed. dRVVT LA1/LA2 was abnormal in 35 (50.7%) patients taking DOACs. The APTT ratio was normal in all studied subjects. DOAC-Stop completely removed dabigatran and reduced by 98% rivaroxaban and by 92.3% apixaban concentrations (all p<0.05). After DOAC-Stop screening dRVVT remained prolonged in 34 (49.3%) patients (p<0.001), while dRVVT LA1/LA2 was abnormal in six (8.7%) subjects, with no association with DOAC concentrations at baseline and after DOAC-Stop. The APTT-LA screening test remained prolonged in five (7.2%) patients, while the APTT LA1/LA2 ratio was normal in those subjects. DOAC-Stop did not influence LA testing in APS patients. Conclusions Application of DOAC-Stop effectively reduced plasma DOAC concentrations leading to appropriate dRVVT results in up to 97% of VTE patients.

Topics: Administration, Oral; Adult; Anticoagulants; Antiphospholipid Syndrome; Blood Coagulation; Blood Coagulation Tests; Dabigatran; Factor Xa Inhibitors; False Positive Reactions; Female; Humans; Lupus Coagulation Inhibitor; Male; Middle Aged; Partial Thromboplastin Time; Plasma; Prothrombin Time; Pyrazoles; Pyridones; Rivaroxaban; Venous Thromboembolism

Topics: Animals; Aorta; Factor Xa Inhibitors; Male; Nitric Oxide; Pyrazoles; Pyridones; Rats, Sprague-Dawley; Rivaroxaban; Vasodilation

There is a high degree of uncertainty regarding optimum care of patients with potential or known intake of oral anticoagulants and traumatic brain injury (TBI). Anticoagulation therapy aggravates the risk of intracerebral hemorrhage but, on the other hand, patients take anticoagulants because of an underlying prothrombotic risk, and this could be increased following trauma. Treatment decisions must be taken with due consideration of both these risks. An interdisciplinary group of Austrian experts was convened to develop recommendations for best clinical practice. The aim was to provide pragmatic, clear, and easy-to-follow clinical guidance for coagulation management in adult patients with TBI and potential or known intake of platelet inhibitors, vitamin K antagonists, or non-vitamin K antagonist oral anticoagulants. Diagnosis, coagulation testing, and reversal of anticoagulation were considered as key steps upon presentation. Post-trauma management (prophylaxis for thromboembolism and resumption of long-term anticoagulation therapy) was also explored. The lack of robust evidence on which to base treatment recommendations highlights the need for randomized controlled trials in this setting.

Topics: Administration, Oral; Anticoagulants; Austria; Brain Injuries, Traumatic; Consensus; Dabigatran; Deamino Arginine Vasopressin; Humans; Interdisciplinary Communication; Partial Thromboplastin Time; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thromboembolism; Tomography, X-Ray Computed; Tranexamic Acid; Treatment Outcome; Vitamin K

Label adherence for non-vitamin K antagonist oral anticoagulants (NOACs) has not been well evaluated in Asian patients with non-valvular atrial fibrillation (AF). The present study aimed to assess label adherence for NOACs in a Korean AF population and to determine risk factors of off-label prescriptions of NOACs.. In this COmparison study of Drugs for symptom control and complication prEvention of AF (CODE-AF) registry, patients with AF who were prescribed NOACs between June 2016 and May 2017 were included. Four NOAC doses were categorized as on- or off-label use according to Korea Food and Drug Regulations.. We evaluated 3080 AF patients treated with NOACs (dabigatran 27.2%, rivaroxaban 23.9%, apixaban 36.9%, and edoxaban 12.0%). The mean age was 70.5±9.2 years; 56.0% were men; and the mean CHA₂DS₂-VASc score was 3.3±1.4. Only one-third of the patients (32.7%) was prescribed a standard dose of NOAC. More than one-third of the study population (n=1122, 36.4%) was prescribed an off-label reduced dose of NOAC. Compared to those with an on-label standard dosing, patients with an off-label reduced dose of NOAC were older (≥75 years), women, and had a lower body weight (≤60 kg), renal dysfunction (creatinine clearance ≤50 mL/min), previous stroke, previous bleeding, hypertension, concomitant dronedarone use, and anti-platelet use.. In real-world practice, more than one-third of patients with NOAC prescriptions received an off-label reduced dose, which could result in an increased risk of stroke. Considering the high risk of stroke in these patients, on-label use of NOAC is recommended.

Topics: Administration, Oral; Aged; Anticoagulants; Asian People; Atrial Fibrillation; Dabigatran; Drug Labeling; Female; Humans; Male; Medication Adherence; Middle Aged; Prospective Studies; Pyrazoles; Pyridines; Pyridones; Republic of Korea; Risk Factors; Rivaroxaban; Thiazoles; Vitamin K

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

Background Liver cirrhotic patients with nonvalvular atrial fibrillation have been excluded from randomized clinical studies regarding oral anticoagulants for stroke prevention. Whether non-vitamin K antagonist oral anticoagulants ( NOAC s) are superior to warfarin for these patients remains unclear. Methods and Results This nationwide retrospective cohort study, with data collected from the Taiwan National Health Insurance Research Database, enrolled 2428 liver cirrhotic patients with nonvalvular atrial fibrillation taking apixaban (n=171), dabigatran (n=535), rivaroxaban (n=732), or warfarin (n=990) from June 1, 2012, to December 31, 2016. We used propensity score-based stabilized weights to balance covariates across study groups. Patients were followed until the occurrence of an event or the end date of study. The NOAC group (n=1438) showed risk of ischemic stroke/systemic embolism and intracranial hemorrhage comparable to that of the warfarin group (n=990) after adjustment. The NOAC group showed significantly lower risk of gastrointestinal bleeding (hazard ratio: 0.51 [95% CI, 0.32-0.79]; P=0.0030) and all major bleeding (hazard ratio: 0.51 [95% CI, 0.32-0.74]; P=0.0003) compared with warfarin group. Overall, 90% (n=1290) of patients were taking a low-dose NOAC (apixaban 2.5 mg twice daily, rivaroxaban 10-15 mg daily, or dabigatran 110 mg twice daily). The subgroup analysis indicated that both dabigatran and rivaroxaban showed lower risk of all major bleeding than warfarin. The advantage of lower gastrointestinal and all major bleeding with NOACs over warfarin is contributed by those subgroups with either nonalcoholic or nonadvanced liver cirrhosis. Conclusions NOACs have a risk of thromboembolism comparable to that of warfarin and a lower risk of major bleeding among liver cirrhotic Asian patients with nonvalvular atrial fibrillation. Consequently, thromboprophylaxis with low-dose NOAC s may be considered for such patients.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Female; Hemorrhage; Humans; Liver Cirrhosis; Male; Middle Aged; Patient Safety; Pyrazoles; Pyridones; Retrospective Studies; Risk Assessment; Risk Factors; Rivaroxaban; Stroke; Taiwan; Thromboembolism; Time Factors; Treatment Outcome; Warfarin

BACKGROUND The Jessa Atrial Fibrillation Knowledge Questionnaire (JAKQ) was successfully used to assess knowledge gaps in patients with atrial fibrillation (AF). AIMS To evaluate the regional differences among Polish patients in their awareness of AF diagnosis and oral anticoagulation use. METHODS A total of 1583 patients with AF at a median (IQR) age of 72 (66-79) years completed the JAKQ in 3 cardiology centers (center I, Kraków; center II, Toruń; center III, Kielce) from January 2017 to June 2018. The final analysis included 1525 patients, 32.9% were on vitamin K antagonists (VKAs) and 67.1% on non-VKA oral anticoagulants (NOACs), that is, rivaroxaban and dabigatran (28.9% each), and apixaban (9.3%). RESULTS The mean (SD) score on the JAKQ was 55.5% (18.4%) with better results among patients on VKAs compared with NOACs (58% [18.3%] vs 54.3% [18.4%]; P = 0.0002) with time from AF diagnosis more than 12 months (57.4% [17.5%] vs 50% [19.9%]; P <0.0001). There was a significant difference in the knowledge scores between the 3 centers (I, 59.5%; II, 48.5%; III, 54.3%; P <0.0001). In all centers the number of correct answers correlated inversely with patient's age (r = -0.20; P <0.0001). NOACs were more frequently used in center III. The percentage of correct responses was lower in patients on reduced NOAC doses (35.4% of patients on NOACs), compared with the full-dose NOAC groups in center I (56.9% vs 62.5%; P = 0.012) and II (48.1% vs 56.2%; P = 0.003). CONCLUSIONS Patients from a high-volume academic center showed better knowledge than their peers from district hospitals. There are large regional differences in prescription patterns of oral anticoagulants, including the preferred NOAC.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Disease Management; Female; Hospitals, District; Hospitals, Teaching; Humans; Male; Patient Education as Topic; Patient Medication Knowledge; Poland; Pyrazoles; Pyridones; Rivaroxaban; Surveys and Questionnaires

Elderly patients with atrial fibrillation (AF) are known to have a high risk of stroke and bleeding. We investigated the effectiveness and safety of non-vitamin K antagonist oral anticoagulants (NOACs) in octogenarian patients with non-valvular AF compared with warfarin.. A total of 687 octogenarian patients with AF who were administered NOACs (n = 403) or warfarin (n = 284) for stroke prevention between 2012 and 2016 were included. Thromboembolic (TE) events (stroke or systemic embolism), major bleeding events, and all-cause death were analyzed.. The NOACs group (age 83.4±3.2 years, women 52.4%, CHA2DS2-VASc score 5.0±1.8) comprised 141 dabigatran, 158 rivaroxaban, and 104 apixaban users. Most patients from the NOACs group had been prescribed a reduced dose of medication (85.6%). During 14±18 months of follow-up periods, there were 19 TE events and 18 major bleeding events. Patients with NOAC showed a lower risk of TE (1.84 vs. 2.71 per 100 person-years, hazard ration [HR] 0.134, 95% confidence interval [CI] 0.038-0.479, P = 0.002), major bleeding (1.48 vs. 2.72 per 100 person-years, HR 0.110, 95% CI 0.024-0.493, P = 0.001), and all-cause death (2.57 vs. 3.50 per 100 person-years, HR 0.298, 95% CI 0.108-0.824, P = 0.020).. In octogenarian Asian patients with AF, NOACs might be associated with lower risks of thromboembolic events, major bleeding, and all-cause death than warfarin. Although most patients had received reduced doses, on-label use of NOACs was effective and safe.

Topics: Administration, Oral; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Treatment Outcome; Warfarin

Apixaban and rivaroxaban are approved for the prevention and treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and embolic stroke in atrial fibrillation (AF) patients. The aim of this study was to find appropriate methods of monitoring the anticoagulant effects of are direct oral anticoagulants (DOACs) and establish on-therapy ranges using conventional tests.. A total of 184 samples were collected from 91 patients receiving DOACs. Concentrations of apixaban and rivaroxaban in plasma were accessed by an anti-factor Xa chromogenic assay. PT, APTT, antithrombin, D-dimer, dRVVT screen/confirm, FDP, and fibrinogen levels were measured. On-therapy ranges were calculated by substituting previously reported trough plasma concentrations of DOACs.. Anti-factor Xa chromogenic assay-based DOACs levels were 26.0-279.5 (115.9 ± 56.5) ng/mL for apixaban at 2.5 mg BID, 19.9-565.1 (205.3 ± 162.4) ng/mL for apixaban at 5 mg BID, 2.3-395.3 (205.3 ± 162.4) ng/mL for rivaroxaban at 15 mg OD, 3.6-494.8 (119.6 ± 95.1) ng/mL for rivaroxaban at 20 mg OD, and 9.6-431.4 (140.8 ± 113.6) ng/mL for rivaroxaban at 15 mg BID. PT (%), antithrombin, and dRVVT confirm tests showed good correlation with plasma apixaban levels. Plasma rivaroxaban concentrations were correlated well with PT (sec), PT (%),and dRVVT confirm results. On-therapy ranges established for dRVVT confirm test by linear regression were as follows: 1.32-1.52 for apixaban 2.5 mg BID, 1.12-1.75 for apixaban 5 mg BID, 1.11-1.78 for rivaroxaban 15 mg OD, 1.09-1.64 for rivaroxaban 20 mg OD, and 1.22-1.81 for rivaroxaban 20 mg BID.. Apixaban concentrations were well correlated with PT (%), antithrombin, and dRVVT confirm test. Rivaroxaban concentrations showed good correlation with PT (sec), PT (%), and dRVVT confirm test.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Blood Coagulation Tests; Clinical Laboratory Techniques; Factor Xa Inhibitors; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Humans; Male; Middle Aged; Prothrombin Time; Pyrazoles; Pyridones; Rivaroxaban; Viper Venoms

Topics: Atrial Fibrillation; Dabigatran; Humans; Pyrazoles; Pyridones; Rivaroxaban; Vitamin K

Differences in adherence may represent drug properties (e.g. dosing interval) or patient experiences while on treatment. Adherence to direct oral anticoagulants (DOACs) in nonvalvular atrial fibrillation (NVAF) is important to maintain effectiveness over the course of treatment.. This was a retrospective cohort study using 2009-2015 Truven Health MarketScan Databases. New initiators of dabigatran, rivaroxaban, and apixaban with NVAF were identified. Twelve months of continuous enrollment before treatment was required to assess demographics and medical history. Proportion of days cover (PDC) was used to measure adherence at 3, 6, 9 and 12-month. Gaps in therapy and treatment switches were also evaluated. Logistic regression was used to compare high adherence (PDC ≥0.80).. A total of 14,864 dabigatran, 16,005 rivaroxaban, and 8078 apixaban users were identified. Apixaban users had the highest adherence overall, with mean PDC at 3, 6, 9, and 12-months of 0.83, 0.76, 0.72, and 0.69, while dabigatran had the lowest adherence of 0.78, 0.67, 0.61, and 0.57. Adherence to DOACs increased with increased stroke risk scores. Adherence was also higher when first days supplied was > 30 days compared to 30 days and when filled via mail order pharmacies. Switching was highest among dabigatran users. Apixaban users were the most likely to have high adherence versus dabigatran (OR = 1.73, 95% CI = 1.60-1.88) and versus rivaroxaban (OR = 1.24, 95% CI = 1.14-1.34) at 12-months.. Apixaban users had the highest overall adherence despite twice-daily dosing versus once-daily dosing for rivaroxaban. These findings can be useful for formulary decision-making and when assessing treatment options.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antithrombins; Atrial Fibrillation; Dabigatran; Databases, Factual; Drug Administration Schedule; Drug Substitution; Factor Xa Inhibitors; Female; Humans; Male; Medication Adherence; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Time Factors; Treatment Outcome

 This study assessed changes in anticoagulation therapy over time in patients with atrial fibrillation (AF)..  Analyses were performed on a claims-based dataset of 4 million health-insured individuals. The study population consisted of patients newly initiating a non-vitamin-K oral anticoagulants (NOACs) or vitamin K antagonist (VKA) for AF between 2013 and 2016. The study outcomes consisted of the proportion of patients who had (1) discontinued OAC treatment, (2) switched from VKA to NOAC, (3) switched from NOAC to VKA or (4) switched from one NOAC to another. Predictors of discontinuation or switching of OAC treatment were determined by Cox proportional hazards regression models with time-independent and time-dependent covariates..  The study population comprised 51,606 AF patients initiating VKA (.  Overall discontinuation rates of VKA and NOACs are comparable over the first year of therapy, while switching from VKA to NOAC was more common than from NOAC to VKA. The majority of treatment changes were associated with clinical events.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Drug Substitution; Female; Follow-Up Studies; Germany; Hemorrhage; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Vitamin K; Withholding Treatment

Geriatric characteristics such as high age, multi-morbidity, polypharmacy and frailty are common in patients with atrial fibrillation (AF). In a retrospective study using a German claims database, effectiveness (ischaemic stroke/systemic embolism) and safety (intracerebral, gastrointestinal and major extracranial bleeding) were compared in patients with non-valvular AF starting non-vitamin K oral antagonists (NOACs) (apixaban, dabigatran and rivaroxaban) and phenprocoumon. Cox proportional hazards models were used to calculate adjusted hazard ratios, and interaction terms of the treatment group and geriatric status (defined by age ≥75 years, frailty, ≥ 4 co-morbidities and polypharmacy) were entered into the model. A total of 42,562 and 27,939 patients initiated NOAC and phenprocoumon treatment (mean age 74 years ± 11, 51% male) with a follow-up time of 147,785 person-years. Note that 52.9% of patients were elderly, 50.8% were frail, 37.0% were co-morbid and 46.5% had polypharmacy. NOAC use was not associated with effectiveness and gastrointestinal bleeding, neither in geriatric nor in non-geriatric patients. The hazard of major extracranial and intracranial bleeding was significantly decreased for NOAC use, with similar risk reduction in geriatric and non-geriatric patients: major extracranial bleeding 0.70 (95% confidence interval [CI], 0.56-0.87) to 0.73 (95% CI, 0.60-0.89) for the geriatric groups and 0.71 (95% CI, 0.56-0.93) to 0.76 (0.59-0.98) for the non-geriatric groups (

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Geriatrics; Germany; Humans; Middle Aged; Phenprocoumon; Proportional Hazards Models; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Vitamin K

In the treatment of non-valvular atrial fibrillation (AF) with oral anticoagulants (OAC), medical adherence is a relevant factor for stroke prevention.. To evaluate the one-year persistence of vitamin K antagonists (VKA) and direct oral anticoagulants (DOAC) in patients suffering from AF and already treated with OACs.. Information from the National Health Insurance Fund of Hungary prescriptions database on pharmacy claims between June 1, 2015 and December 31, 2015 was analysed. Authors identified patients who filled prescriptions for OACs (VKAs or DOACs) prescribed for AF who have already received OACs therapy during one year before. Apparatus of survival analysis was used, where 'survival' was the time to abandon the medication.. 196 016 patients met the inclusion criteria. 181 810 patients received VKA and 14 206 patients were treated with DOACs. The one-year persistence rate in patients taking VKA was 52.9% whereas it was 66.8% in those on the DOACs. The persistence rates after 360 days were 67.5% for rivaroxaban, 63.6% for apixaban and 63.4% for dabigatran. The mean duration of persistence was 311 days for rivaroxaban, 308 days for apixaban and 284 days for dabigatran. The actual rate of discontinuation was 14% (HR = 1.14 [95% CI 1.05-1.24]), p = 0.0015) for apixaban, 15% (HR = 1.15 [95% CI 1.08-1.23], p = 0.003) for dabigatran and 62% (HR = 1.62 [95% CI 1.56-1.69], p<0.0001) for VKA compared to rivaroxaban (reference).. The authors have confirmed that the one-year persistence of DOAKs was significantly higher compared to KVA therapy in AF. The one-year persistence of rivaroxaban was more favoured than apixaban and dabigatran. Orv Hetil. 2019; 160(13): 509-515.. Absztrakt: Bevezetés: A nonvalvularis pitvarfibrilláció (PF) orális antikoagulánssal (OAK) történő kezelésekor a terápiahűség igen jelentős tényező a stroke prevenciójában. Célkitűzések: A szerzők célja a már OAK-terápiában részesülő PF-ban szenvedő betegeknél a K-vitamin-antagonista (KVA) és a direkt orális antikoagulánsok (DOAK) egyéves perzisztenciájának vizsgálata. Módszer: A Nemzeti Egészségbiztosítási Alapkezelő adatbázisából a vényforgalmi adatokra támaszkodva pitvarfibrilláció indikációjában, 2015 második félévében valamely orális antikoaguláns (OAK = KVA/DOAK) receptjét kiváltó olyan betegeket választottak ki, akiknek a vizsgálati időszakot megelőzően – a vizsgálati időszakban történt kiváltási dátumhoz képest – 12 hónappal korábban volt (DOAK/KVA összes) vénykiváltásuk. A perzisztencia modellezésére a túlélés-analízis klasszikus eszköztárát alkalmazták, ahol a „túlélési” idő a gyógyszer szedésének abbahagyásáig eltelt idő volt, 60 napos ’grace’ periódussal. Eredmények: A bevonási kritériumoknak 196 016 beteg felelt meg. A betegek közül 181 810 szedett KVA-t, míg 14 206 beteg kapott DOAK-ot. A KVA-k egyéves perzisztenciája 52,9%, a DOAK-ot szedőké 66,8% volt. A DOAK-terápián belül a rivaroxaban egyéves perzisztenciája 67,5%, az apixabané 63,6%, a dabigatrané 63,4% volt. A 360 napra korlátozott átlagos gyógyszerszedési idő 311 nap volt a rivaroxaban, 308 nap az apixaban, 303 nap a dabigatran, míg 284 nap a KVA-k esetén. A gyógyszerelhagyás kockázatának pillanatnyi rátája az apixaban esetén 14%-kal (HR = 1,14 [95% CI 1,05–1,24]), p = 0,0015), a dabigatrannál 15%-kal (HR = 1,15 [95% CI 1,08–1,23], p = 0,003), a KVA-t szedőknél 62%-kal (HR = 1,62 [95% CI 1,56–1,69], p<0,0001) volt magasabb a rivaroxabanhoz képest. Következtetés: A szerzők igazolták, hogy PF-ban a KVA-terápiához képest a DOAK-ok egyéves perzisztenciája szignifikánsan magasabb volt. A DOAK-ok közül a rivaroxaban egyéves perzisztenciája előnyösebbnek bizonyult az apixabanhoz és a dabigatranhoz képest. Orv Hetil. 2019; 160(13): 509–515.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Databases, Factual; Humans; Hungary; Pyrazoles; Pyridones; Rivaroxaban; Treatment Outcome; Vitamin K

Direct oral anticoagulants (DOACs) are at least as efficacious and safe as warfarin among non-valvular atrial fibrillation (NVAF) patients; limited evidence is available regarding NVAF patients with heart failure (HF). US Medicare enrollees with NVAF and HF initiating DOACs (apixaban, rivaroxaban, dabigatran) or warfarin were selected. Propensity score matching and Cox models were used to estimate the risk of stroke/systemic embolism (SE), major bleeding (MB), and major adverse cardiac events (MACE) comparing DOACs versus warfarin and DOACs versus DOACs. We identified 10,570 apixaban-warfarin, 4,297 dabigatran-warfarin, 15,712 rivaroxaban-warfarin, 4,263 apixaban-dabigatran, 10,477 apixaban-rivaroxaban, and 4,297 dabigatran-rivaroxaban matched pairs. Compared to warfarin, apixaban had lower rates of stroke/SE (hazard ratio = 0.64, 95% confidence interval = 0.48-0.85), MB (hazard ratio = 0.66, 0.58-0.76), and MACE (hazard ratio = 0.73,0.67-0.79); dabigatran and rivaroxaban had lower rates of MACE (hazard ratio = 0.87,0.77-0.99; hazard ratio = 0.84, 0.79-0.89, respectively). Rivaroxaban had a lower stroke/SE rate (hazard ratio = 0.65, 0.52-0.81) and higher MB rate (hazard ratio = 1.18, 1.08-1.30) versus warfarin. Compared to dabigatran and rivaroxaban, apixaban had lower MB (hazard ratio = 0.71, 0.57-0.89; hazard ratio = 0.55, 0.49-0.63) and MACE rates (hazard ratio = 0.80, 0.69-0.93; hazard ratio = 0.86, 0.79-0.94), respectively. All DOACs had lower MACE rates versus warfarin; differences were observed in stroke/SE and MB. Our findings provide insights about OAC therapy among NVAF patients with HF.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Heart Failure; Humans; Incidence; Kaplan-Meier Estimate; Male; Medicare; Patient Safety; Proportional Hazards Models; Pyrazoles; Pyridones; Retrospective Studies; Risk; Rivaroxaban; Treatment Outcome; United States; Warfarin

Atrial fibrillation (AF) prevalence increases with age; > 80% of US adults with AF are aged ≥ 65 years. Compare the risk of stroke/systemic embolism (SE), major bleeding (MB), net clinical outcome (NCO), and major adverse cardiac events (MACE) among elderly non-valvular AF (NVAF) Medicare patients prescribed direct oral anticoagulants (DOACs) VS warfarin. NVAF patients aged ≥ 65 years who initiated DOACs (apixaban, dabigatran, and rivaroxaban) or warfarin were selected from 01JAN2013-31DEC2015 in CMS Medicare data. Propensity score matching was used to balance DOAC and warfarin cohorts. Cox proportional hazards models estimated the risk of stroke/SE, MB, NCO, and MACE. 37,525 apixaban-warfarin, 18,131 dabigatran-warfarin, and 55,359 rivaroxaban-warfarin pairs were included. Compared to warfarin, apixaban (HR: 0.69; 95% CI 0.59-0.81) and rivaroxaban (HR: 0.82; 95% CI 0.73-0.91) had lower risk of stroke/SE, and dabigatran (HR: 0.88; 95% CI 0.72-1.07) had similar risk of stroke/SE. Apixaban (MB: HR: 0.61; 95% CI 0.57-0.67; NCO: HR: 0.64; 95% CI 0.60-0.69) and dabigatran (MB: HR: 0.79; 95% CI 0.71-0.89; NCO: HR: 0.84; 95% CI 0.76-0.93) had lower risk of MB and NCO, and rivaroxaban had higher risk of MB (HR: 1.08; 95% CI 1.02-1.14) and similar risk of NCO (HR: 1.04; 95% CI 0.99-1.09). Compared to warfarin, apixaban had a lower risk for stroke/SE, MB, and NCO; dabigatran had a lower risk of MB and NCO; and rivaroxaban had a lower risk of stroke/SE but higher risk of MB. All DOACs had lower risk of MACE compared to warfarin.

Topics: Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Cardiovascular Diseases; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Medicare; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Treatment Outcome; United States; Warfarin

Topics: Humans; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Venous Thromboembolism

Topics: Humans; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Venous Thromboembolism

Topics: Humans; Pyrazoles; Pyridones; Rivaroxaban; Venous Thromboembolism

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

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

Essentials Direct oral anticoagulants (DOAC) are used for stroke and venous thromboembolism prevention. We report a new assay that measures anti-factor Xa DOAC levels in plasma and whole blood. Rivaroxaban and apixaban can be accurately quantified below trough levels. The ease and accuracy of the assay demonstrate its potential for point-of-care applications.. Rivaroxaban and apixaban are the most commonly used anti-factor (F) Xa direct oral anticoagulants (DOAC), with indications for prevention of stroke in nonvalvular atrial fibrillation as well as treatment and prevention of venous thromboembolism. However, lacking is accessibility to a detection method that is able to quantify low levels of anti-FXa DOACs.. We report a new assay that measures anti-FXa DOAC levels in plasma and whole blood.. This is achieved by the use of a prothrombin derivative that is labeled with a fluorescent probe (Flu-II), which then acts as the macromolecular substrate to measure residual FXa activity. The Flu-II cleavage is then initiated by the addition of a solution containing FXa, FVa, and phospholipid vesicles composed of 75% PC and 25% PS (PCPS) vesicles with calcium, in the presence of hirudin to prevent feedback activity by the native thrombin generated. The Flu-II cleavage is monitored by fluorescence in real time where the initial rate of fluorescence change is inversely proportional to DOAC levels.. In plasma systems, the assay demonstrates dose-response between 0 and 5 nmol/L rivaroxaban and between 0 and 10 nmol/L apixaban. Corn trypsin inhibitor did not affect this assay. With individual plasma samples, the assay showed excellent consistency and reproducibility. From 2 μL of whole blood, the assay showed dose-response between 0 and 2 nmol/L of DOACs in the final mixture of 100 μL, thus representing up to 100 nmol/L in circulating blood.. The assay is ideal for rapidly and accurately measuring DOAC levels in plasma and blood, demonstrating its potential for point-of-care applications.

Topics: Administration, Oral; Drug Monitoring; Factor Xa Inhibitors; Fluorescent Dyes; Humans; Limit of Detection; Predictive Value of Tests; Pyrazoles; Pyridones; Reproducibility of Results; Rivaroxaban; Spectrometry, Fluorescence

Essentials Currently, DOACs are given at fixed doses and do not require laboratory monitoring. Direct oral anticoagulant-specific measurements were performed at trough and peak. Patients who developed bleeding events showed higher DOAC plasma levels at peak. This study suggests the need of a more accurate DOAC dose assessment.. Direct oral anticoagulants (DOACs) are administered at fixed dose. The aim of the study was to evaluate the relationship between DOAC C-trough or C-peak plasma levels and bleeding complications in patients with non-valvular atrial fibrillation (NVAF).. Five hundred sixty five consecutive naive NVAF patients were enrolled. The DOAC measurements at C-trough and at C-peak (available in 411 patients) were performed at steady state, within the first month of treatment. Major bleeding (MB), clinically relevant non-major bleeding (CRNMB), and minor bleeding (MinB), occurring during 1 year of follow-up after blood sampling, were recorded. For each DOAC, interval of C-trough and C-peak levels was subdivided into four equal classes and results were attributed to these classes; the median values of results were also calculated.. Two hundred eight patients were on apixaban, 185 on dabigatran, and 172 on rivaroxaban. For 1-[qqqdeletezzz] year follow up for all patients, we observed: 19 MB (3.36%), 6 CRNMB (1.06%), and 47 MinB (8.31%). The prevalence of bleeding patients with anticoagulant levels in the upper classes of C-peak activity (II + III + IV) was higher than that in the lowest class. Normalized results of C-peak levels were higher in patients with bleeding than in those without bleeding.. Bleeding complications during DOAC treatment were more frequent among atrial fibrillation (AF) patients with higher C-peak anticoagulant levels. In addition to a previous study that showed an increased risk of thrombotic complications in the patients with low C-trough levels, this study seems to indicate that patients with NVAF on DOACs would need a more accurate definition of their optimal therapeutic window.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antithrombins; Atrial Fibrillation; Blood Coagulation; Dabigatran; Dose-Response Relationship, Drug; Drug Monitoring; Female; Hemorrhage; Humans; Italy; Male; Middle Aged; Pyrazoles; Pyridones; Registries; Risk Factors; Rivaroxaban; Treatment Outcome

The aim of this study was to compare effectiveness and safety of low-strength and high-strength direct oral anticoagulants (DOACs) with warfarin in the Australian Veteran population.. Sequential cohort study using inverse probability of treatment weighting (IPTW) and propensity score matching. Initiators of high-strength (apixaban 5 mg, dabigatran 150 mg, rivaroxaban 20 mg) and low-strength DOACS (apixaban 2.5 mg, dabigatran 110 mg, rivaroxaban 15 mg) were compared with warfarin initiators.. Australian Government Department of Veterans' Affairs claims database.. 4836 patients who initiated oral anticoagulants (45.8%, 26.0% and 28.2% on low-strength, high-strength DOACs and warfarin, respectively) between August 2013 and March 2015. Mean age was 85, 75 and 83 years for low-strength, high-strength DOACs and warfarin initiators, respectively.. One-year risk of hospitalisation for ischaemic stroke, any bleeding event or haemorrhagic stroke. Secondary outcomes were 1-year risk of hospitalisation for myocardial infarction and death.. Using the IPTW method, no difference in risk of ischaemic stroke or bleeding was found with low-strength DOACs compared with warfarin. As a class, no increased risk of myocardial infarction was found for low-strength DOACs, however, risk was elevated for apixaban (HR 2.25, 95% CI 1.23 to 4.13). For high-strength DOACs, no difference was found for ischaemic stroke compared with warfarin, however, there was a significant reduction in risk of bleeding events (HR 0.63, 95% CI 0.44 to 0.89) and death (HR 0.40, 95% CI 0.28 to 0.58). Propensity score matching showed no difference in risk of ischaemic stroke or bleeding.. We found that in the practice setting both DOAC formulations were similar to warfarin with regard to effectiveness and had no increased risk of bleeding.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Australia; Comparative Effectiveness Research; Dabigatran; Databases, Factual; Female; Hemorrhage; Humans; Logistic Models; Male; Myocardial Infarction; Propensity Score; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Veterans; Warfarin

Patients with non-valvular atrial fibrillation (NVAF) and chronic kidney disease (CKD) are at increased risk of stroke and bleeding. Although direct oral anticoagulant (DOAC) trials excluded patients with severe CKD, a growing portion of CKD patients have been starting DOACs and limited data from real-world outcome in this high-risk setting are available. The INSigHT registry included 632 consecutive NVAF patients that started apixaban (256 patients, 41%), dabigatran (245, 39%) and rivaroxaban (131, 20%) between 2012 and 2015. Based on creatinine clearance, two sub-cohorts were defined: (1) non-CKD group (CrCl 60-89 mL/min, 413 patients) and (2) CKD group (15-59 ml/min, 219). Compared to non-CKD patients, those with CKD, were at higher ischemic (CHA

Topics: Administration, Oral; Aged; Atrial Fibrillation; Dabigatran; Factor Xa Inhibitors; Female; Humans; Italy; Male; Middle Aged; Pyrazoles; Pyridones; Registries; Renal Insufficiency, Chronic; Rivaroxaban; Statistics, Nonparametric; Treatment Outcome

Andexanet alfa, a recombinant modified human "decoy" factor Xa (FXa) protein, is the first and only available antidote approved by the Food and Drug Administration to manage life-threatening or uncontrolled bleeding associated with the anti-Xa agents. It binds to direct and indirect anti-Xa oral anticoagulants with high specificity to reverse their inhibitory effects and restore the activity of FXa. Andexanet alfa is administered via two different dosing regimens, standard and high dose, based on the specific FXa inhibitor, dose, and time since the patient's last dose of FXa inhibitor. The approval for andexanet alfa is supported by data from two phase 3 studies (ANNEXA-A, ANNEXA-R) and preliminary data from the phase 3b/4 ANNEXA-4 trial. The first study found that andexanet alfa rapidly reduced anti-Xa activity by 92%-94% in healthy volunteers taking apixaban or rivaroxaban. The ANNEXA-4 study found that the median anti-Xa activity decreased by 89%-93% in patients with major bleeding taking apixaban or rivaroxaban. However, thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up in ANNEXA-4. Additionally, only 40% of patients had restarted anticoagulation and, in this group, the rate of thrombotic events was 12%. Four patients had a thrombotic event within 3 days after andexanet alfa treatment. The wholesale acquisition cost of the standard dose regimen is $24,750, and the high-dose regimen is $49,500. The estimated annual drug budget of treating 10-100 patients ranges from $248K to $495M. Effective October 1, 2018, Medicare will provide an add-on payment for andexanet alfa of up to $14,063 per qualifying case to Inpatient Prospective Payment System-participating acute care hospitals. In this formulary review for a health system's pharmacy and therapeutics committee, andexanet alfa clinical trials and medication package insert were summarized and, after consulting with clinical experts from our institutions, practical recommendations for use were generated to ensure appropriate and safe use of this agent.

Topics: Antidotes; Blood Coagulation; Clinical Trials as Topic; Drug and Narcotic Control; Drug Costs; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Medicare; Medication Therapy Management; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban; United States

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

Rivaroxaban (RIV) is a direct oral anticoagulant (DOAC) targeting activated coagulation factor X (FXa). An earlier study reported the F174A mutant of FXa resistant to a RIV-like inhibitor, Apixaban. In current study, the detailed molecular mechanism of the resistance has been explored by molecular dynamics simulations on the impaired interactions between RIV and FXa in the damaged S4 pocket of F174A mutant. Besides, an unexpected relative stable binding mode of S1'S1 was revealed, which required dynamic motions of Gln192 and Gln61 to allow the morpholinone moiety of RIV to shift into the S1' pocket and form strong interactions. These dynamic motions of RIV and critical residues might be important in drug design for direct inhibitors of coagulation factors.

Topics: Amino Acid Sequence; Anticoagulants; Binding Sites; Drug Design; Factor X; Factor Xa Inhibitors; Humans; Molecular Dynamics Simulation; Mutant Proteins; Protein Binding; Protein Conformation; Pyrazoles; Pyridones; Rivaroxaban; Structure-Activity Relationship

Older adult patients are underrepresented in clinical trials comparing non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin. This subgroup analysis of the ARISTOPHANES study used multiple data sources to compare the risk of stroke/systemic embolism (SE) and major bleeding (MB) among very old patients with nonvalvular atrial fibrillation (NVAF) prescribed NOACs or warfarin.. Retrospective observational study.. The Centers for Medicare & Medicaid Services and three US commercial claims databases.. A total of 88 582 very old (aged ≥80 y) NVAF patients newly initiating apixaban, dabigatran, rivaroxaban, or warfarin from January 1, 2013, to September 30, 2015.. In each database, six 1:1 propensity score matched (PSM) cohorts were created for each drug comparison. Patient cohorts were pooled from all four databases after PSM. Cox proportional hazards models were used to estimate hazard ratios (HRs) of stroke/SE and MB.. The patients in the six matched cohorts had a mean follow-up time of 7 to 9 months. Compared with warfarin, apixaban (HR = .58; 95% confidence interval [CI] = .49-.69), dabigatran (HR = .77; 95% CI = .60-.99), and rivaroxaban (HR = .74; 95% CI = .65-.85) were associated with lower risks of stroke/SE. For MB, apixaban (HR = .60; 95% CI = .54-.67) was associated with a lower risk; dabigatran (HR = .92; 95% CI = .78-1.07) was associated with a similar risk, and rivaroxaban (HR = 1.16; 95% CI = 1.07-1.24) was associated with a higher risk compared with warfarin. Apixaban was associated with a lower risk of stroke/SE and MB compared with dabigatran (stroke/SE: HR = .65; 95% CI = .47-.89; MB: HR = .60; 95% CI = .49-.73) and rivaroxaban (stroke/SE: HR = .72; 95% CI = .59-.86; MB: HR = .50; 95% CI = .45-.55). Dabigatran was associated with a lower risk of MB (HR = .77; 95% CI = .67-.90) compared with rivaroxaban.. Among very old NVAF patients, NOACs were associated with lower rates of stroke/SE and varying rates of MB compared with warfarin. J Am Geriatr Soc 67:1662-1671, 2019.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Embolism; Female; Hemorrhage; Humans; Male; Medicare; Proportional Hazards Models; Pyrazoles; Pyridones; Retrospective Studies; Risk Factors; Rivaroxaban; Stroke; Treatment Outcome; United States; Warfarin

Anticoagulant therapy presents iatrogenic effects such as intracerebral hemorrhage (ICH). The latest anticoagulants on the market, direct oral anticoagulants (DOACs) such as apixaban, dabigatran and rivaroxaban, are reported to cause less ICH than other anticoagulants. Next to the ICH area, the thrombin is accumulated and the blood-brain barrier (BBB) is opened. The effects of thrombin on the BBB are largely mediated by the protease activated receptor (PAR) family, especially the PAR-1 isoform. Our hypothesis is that DOACs may limit the effects of thrombin on endothelial cells (of the BBB) alteration by a mechanism probably involving PAR-1 activation. To test this hypothesis in vitro, we used HBEC-5i human brain endothelial cells as a human BBB model. The effects of thrombin under warfarin, heparin, rivaroxaban, apixaban, and dabigatran treatment on endothelial cells were then investigated by measuring of permeability and junction proteins: ZO-1 and VE-cadherin expressions and PAR-1 cleavage. Depending on the anticoagulant used, we observed three profiles of response of the endothelial cells after thrombin exposure: i) dabigatran treatment allowed maintaining the tightness of the endothelial monolayer; ii) other DOACs limited thrombin-induced alteration of the endothelial monolayer; and iii) pretreatment with warfarin and heparin did not protect from thrombin-induced BBB breakdown. Pretreatment with DOACs clearly limited the impact of thrombin on PAR-1 cleavage in our model, contrary to other anticoagulants, associated with ZO-1 and VE-cadherin expressions. In conclusion, DOACs seem to limit the alteration of the monolayer of endothelial cells of the BBB mediated by the thrombin/PAR-1 pathway.

Topics: Administration, Oral; Anticoagulants; Antigens, CD; Blood-Brain Barrier; Cadherins; Cell Line; Cerebral Hemorrhage; Endothelial Cells; Heparin; Humans; Protein Serine-Threonine Kinases; Pyrazoles; Pyridones; Receptor, PAR-1; Rivaroxaban; Thrombin; Warfarin; Zonula Occludens-1 Protein

Direct acting oral anticoagulants (DOACs) are increasingly used as off-label alternatives to vitamin K antagonists for the treatment of left ventricular (LV) thrombus. However, efficacy data is limited to small case series and one meta-analysis of case reports. We aimed to determine the efficacy and safety of DOACs in treatment of LV thrombus utilizing transthoracic echocardiography (TTE) and clinical outcomes. We identified 52 patients (mean age = 64 years, 71% men) treated with a DOAC for LV thrombus (n = 26 apixaban, n = 24 rivaroxaban, and n = 2 dabigatran). Thirty-five of the 52 patients had a follow-up TTE after DOAC initiation. The primary end point was defined as resolution of LV thrombus (in patients with a subsequent TTE), or death, major bleeding requiring transfusion, intracranial hemorrhage, ischemic stroke, or peripheral embolization. An experienced echocardiographer (M.L.M.) reviewed all TTEs for presence or absence of LV thrombus without knowledge of time point or clinical data. Twenty-nine of the 35 (83%) patients who underwent follow-up TTE had resolution of LV thrombus, with a mean duration of 264 days. Of the total study population, there was 1 cardioembolic event (transient ischemic attack) 52 days after initiating DOAC, 3 gastrointestinal bleeds requiring transfusion, and 1 patient with epistaxis requiring transfusion. All patients with a hemorrhagic complication were receiving concomitant antiplatelet therapy. DOAC therapy appears promising for the treatment of LV thrombus. A larger, prospective study is warranted to confirm these results.

Topics: Adult; Aged; Blood Transfusion; Dabigatran; Echocardiography; Epistaxis; Factor Xa Inhibitors; Female; Follow-Up Studies; Gastrointestinal Hemorrhage; Heart Ventricles; Humans; Ischemic Attack, Transient; Male; Middle Aged; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Thrombosis; Ventricular Dysfunction, Left

Because studies of direct oral anticoagulants in patients with venous thromboembolism and non-valvular atrial fibrillation have had minimal representation of morbidly obese patients (ie, body-mass index [BMI] ≥40 kg/m. We did a single-centre, retrospective analysis of chart data for all adult patients aged at least 18 years at Montefiore Medical Center (Bronx, NY, USA) with a BMI of at least 40 kg/m. We obtained data for 795 patients: 150 prescribed apixaban, 326 rivaroxaban, and 319 warfarin. In 366 patients prescribed an anticoagulant for venous thromboembolism, the incidence of recurrent venous thromboembolism was similar between the apixaban, rivaroxaban, and warfarin cohorts (1/47 [2·1%, 95% CI 0·0-6·3], 3/152 [2·0%, 0·0-4·2], and 2/167 [1·2%, 0·0-2·9], respectively; p=0·74). Incidence of major bleeding in this patient group was also similar between the treatment cohorts (1/47 patients on apixaban [2·1%, 95% CI 0·0-6·3], 2/152 on rivaroxaban [1·3%, 0·0-3·1], and 4/167 on warfarin [2·4%, 0·1-4·7]; p=0·77). In 429 patients prescribed an anticoagulant for atrial fibrillation, incidence of stroke was similar between the treatment cohorts (1/103 patients on apixaban [1·0%, 95% CI 0·0-2·9], 4/174 on rivaroxaban [2·3%, 0·1-4·5], and 2/152 on warfarin [1·3%, 0·0-3·1], p=0·71). In this patient group, major bleeding occurred in 3/103 patients on apixaban (2·9%, 95% CI 0·0-6·2), 5/174 on rivaroxaban (2·9%, 0·4-5·4), and 12/152 on warfarin (7·9%, 3·6-12·2); p=0·063. Time-to-event analyses showed that risk of all outcomes in patients with venous thromboembolism, and stroke and composite bleeding in patients with atrial fibrillation, were similar between the anticoagulant cohorts.. Our retrospective study provides further evidence of similar efficacy and safety between the direct oral anticoagulants apixaban and rivaroxaban, and warfarin in morbidly obese patients with atrial fibrillation and venous thromboembolism. These data, if confirmed in prospective studies, might enable patients with a BMI of at least 40 kg/m. None.

Topics: Adult; Aged; Anticoagulants; Atrial Fibrillation; Body Mass Index; Factor Xa Inhibitors; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Obesity, Morbid; Proportional Hazards Models; Pyrazoles; Pyridones; Recurrence; Retrospective Studies; Rivaroxaban; Venous Thromboembolism; Warfarin

Low-molecular-weight heparins (LMWH) are the drug of choice for treatment of cancer-associated thrombosis (CAT), however non-vitamin K antagonist oral anticoagulants (NOAC) seem to be a reasonable alternative. We investigated the safety and efficacy of NOAC versus LMWH in patients with a history of CAT.. In a prospective cohort study 128 consecutive patients with active cancer who experienced CAT were enrolled following LMWH treatment for ≥3 months. Symptomatic recurrent venous thromboembolism (VTE), bleeding and death were recorded during follow-up.. 65 (50.8%) patients were switched to NOAC and 63 (49.2%) continued with LMWH. During a median follow-up of 17 (interquartile range, 15-21) months, recurrent VTE was observed in 6 (9.2%) patients on NOAC and in 12 (19.0%) on LMWH (hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.16-1.16). The rate of major bleeding was 9.2% and 4.8%, respectively (HR 2.00, 95% CI 0.50-8.00). The median time to bleeding was shorter in patients on NOAC (3 [2.25-5.5] months) versus on LMWH (9 [6.5-13.0] months). The mortality rates were similar in both groups (15.4% versus 15.9%, respectively, HR 0.76, 95% CI 0.32-1.84).. In patients following CAT, extended treatment with NOAC, compared with LMWH, appears to be associated with similar effectiveness and safety.

Topics: Administration, Oral; Aged; Anticoagulants; Antithrombins; Comparative Effectiveness Research; Dabigatran; Drug Administration Schedule; Enoxaparin; Female; Hemorrhage; Humans; Male; Middle Aged; Neoplasms; Pilot Projects; Prospective Studies; Pyrazoles; Pyridones; Recurrence; Risk Factors; Rivaroxaban; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

Clinical trials have demonstrated that direct oral anticoagulants (DOACs) are at least non-inferior to warfarin in reducing the risk of stroke/systemic embolism (SE) among patients with non-valvular atrial fibrillation (NVAF), but the comparative risk of major bleeding varies between DOACs and warfarin. Using US Department of Defense (DOD) data, this study compared the risk of stroke/SE and major bleeding for DOACs relative to warfarin.. Adult patients with ≥1 pharmacy claim for apixaban, dabigatran, rivaroxaban, or warfarin from 01 Jan 2013-30 Sep 2015 were selected. Patients were required to have ≥1 medical claim for atrial fibrillation during the 12-month baseline period. Patients with a warfarin or DOAC claim during the 12-month baseline period were excluded. Each DOAC cohort was matched to the warfarin cohort using propensity score matching (PSM). Cox proportional hazards models were conducted to evaluate the risk of stroke/SE and major bleeding of each DOAC vs warfarin.. Of 41,001 identified patients, there were 3691 dabigatran-warfarin, 8226 rivaroxaban-warfarin, and 7607 apixaban-warfarin matched patient pairs. Apixaban was the only DOAC found to be associated with a significantly lower risk of stroke/SE (hazard ratio [HR]: 0.55; 95% confidence interval [CI]: 0.39, 0.77; p < 0.001) and major bleeding (HR: 0.65; 95% CI: 0.53, 0.80; p < 0.001) compared to warfarin. Dabigatran and rivaroxaban initiation were associated with similar risk of stroke/SE (dabigatran: HR: 0.68; 95% CI: 0.43, 1.07; p = 0.096; rivaroxaban: HR: 0.83; 95% CI: 0.64, 1.09; p = 0.187) and major bleeding (dabigatran: HR: 1.05; 95% CI: 0.79, 1.40; p = 0.730; rivaroxaban: HR: 1.07; 95% CI: 0.91, 1.27; p = 0.423) compared to warfarin.. Among NVAF patients in the US DOD population, apixaban was associated with significantly lower risk of stroke/SE and major bleeding compared to warfarin. Dabigatran and rivaroxaban were associated with similar risk of stroke/SE and major bleeding compared to warfarin.

Topics: Administration, Oral; Adolescent; Adult; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Hemorrhage; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Risk Assessment; Risk Factors; Rivaroxaban; Stroke; Treatment Outcome; United States; United States Department of Defense; Warfarin; Young Adult

Topics: Anticoagulants; Atrial Fibrillation; Dabigatran; Humans; Patients; Pyrazoles; Pyridones; Renal Insufficiency, Chronic; Rivaroxaban; Safety

The activation of protease-activated receptor (PAR)-2 by factor Xa (fXa) promotes the release of tissue factor-positive microvesicles (TF

Topics: Adenocarcinoma; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell-Derived Microparticles; Factor VIIa; Factor Xa Inhibitors; Female; Humans; Pancreatic Neoplasms; Pyrazoles; Pyridones; Receptor, PAR-2; Rivaroxaban; Signal Transduction; Thromboplastin

To estimate the incidence of direct oral anticoagulant drug (DOAC) use in patients with nonvalvular atrial fibrillation and to describe user and treatment characteristics in 8 European healthcare databases representing 6 European countries.. Longitudinal drug utilization study from January 2008 to December 2015. A common protocol approach was applied. Annual period incidences and direct standardisation by age and sex were performed. Dose adjustment related to change in age and by renal function as well as concomitant use of potentially interacting drugs were assessed.. A total of 186 405 new DOAC users (age ≥18 years) were identified. Standardized incidences varied from 1.93-2.60 and 0.11-8.71 users/10 000 (2011-2015) for dabigatran and rivaroxaban, respectively, and from 0.01-8.12 users/10 000 (2012-2015) for apixaban. In 2015, the DOAC incidence ranged from 9 to 28/10 000 inhabitants in SIDIAP (Spain) and DNR (Denmark) respectively. There were differences in population coverage among the databases. Only 1 database includes the total reference population (DNR) while others are considered a population representative sample (CPRD, BIFAP, SIDIAP, EGB, Mondriaan). They also varied in the type of drug data source (administrative, clinical). Dose adjustment ranged from 4.6% in BIFAP (Spain) to 15.6% in EGB (France). Concomitant use of interacting drugs varied between 16.4% (SIDIAP) and 70.5% (EGB). Cardiovascular comorbidities ranged from 25.4% in Mondriaan (The Netherlands) to 82.9% in AOK Nordwest (Germany).. Overall, apixaban and rivaroxaban increased its use during the study period while dabigatran decreased. There was variability in patient characteristics such as comorbidities, potentially interacting drugs and dose adjustment. (EMA/2015/27/PH).

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Databases, Factual; Denmark; Dose-Response Relationship, Drug; Drug Interactions; Drug Utilization; Female; France; Germany; Humans; Longitudinal Studies; Male; Metalloporphyrins; Middle Aged; Netherlands; Pyrazoles; Pyridones; Rivaroxaban; Sex Factors; Spain; United Kingdom; Young Adult

Topics: Antidotes; Blood Coagulation Factors; Blood Component Transfusion; Blood Loss, Surgical; Cerebral Hemorrhage; Drug Administration Schedule; Emergencies; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Intraoperative Care; Premedication; Preoperative Care; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban; Wounds and Injuries

This case series presents 3 patients with acute kidney injury taking apixaban or rivaroxaban and transitioning to a heparin infusion.. Case 1 was a 78-year-old man admitted with respiratory failure, acute decompensated heart failure, and acute kidney injury. He was taking apixaban for atrial flutter. He was transitioned to an i.v. heparin infusion and had 2 consecutive heparin antifactor-Xa levels greater than 2 units/mL. Heparin was held and resumed about 36 hours later when the apixaban anti-Xa level was less than 50 ng/mL. Case 2 was a 55-year-old man admitted with acute kidney injury, taking apixaban for a recent deep vein thrombosis. Apixaban anti-Xa levels were monitored and i.v. heparin was initiated when the level was less than 100 ng/mL, about 56 hours after the last apixaban dose. Case 3 was a 64-year-old woman admitted with sepsis and acute kidney injury taking rivaroxaban for pulmonary embolism, which occurred 2 weeks prior to admission. Rivaroxaban anti-Xa levels were monitored and i.v. heparin was initiated about 36 hours after the last dose when the level was less than 100 ng/mL. The management strategy did not lead to any thrombotic outcomes; however, 1 patient experienced bleeding.. Specific anti-Xa levels for rivaroxaban and apixaban appeared to be helpful in the transition of 3 patients to unfractionated heparin infusions in the setting of acute kidney injury. These levels provided enhanced, individualized care and likely helped avoid over and under anticoagulation.

Topics: Acute Kidney Injury; Administration, Oral; Aged; Atrial Flutter; Drug Monitoring; Drug Substitution; Factor Xa Inhibitors; Female; Heparin; Humans; Infusions, Intravenous; Kidney; Male; Middle Aged; Pulmonary Embolism; Pyrazoles; Pyridones; Renal Elimination; Rivaroxaban; Venous Thrombosis

At least four prospective trials have been initiated investigating the direct oral anticoagulants in the antiphospholipid syndrome. Preliminary reports have supported their use in patients with a history of venous thrombosis and a target INR of 2-3, but there have also been reports of failure of these agents in the antiphospholipid syndrome. The objective is to present a case report that illustrates there may be important dosing issues when considering the use of these agents in patients with the antiphospholipid syndrome.. A 50-year-old woman with the antiphospholipid syndrome, manifesting clinically with recurrent pyoderma gangrenosum-like leg ulcers, was treated with apixaban, resulting in improved ulcer healing. For insurance purposes, she was switched to rivaroxaban with worsening of the ulcers which again improved when apixaban was resumed.. Despite a similar half-life, pharmacokinetics and pharmacodynamics, the manufacturer-recommended maintenance dosing of apixaban is twice daily and rivaroxaban once daily. We believe this difference in recommended dose accounts for the differential clinical response noted in the present case report and that twice daily dosing and a larger daily dose of these agents may be more efficacious in potent hypercoagulable disorders, such as the antiphospholipid syndrome.

Topics: Anticoagulants; Antiphospholipid Syndrome; Female; Humans; Middle Aged; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban

After non-vitamin K antagonist (VKA) oral anticoagulation agents (NOAC) have been approved for thrombo-embolic prophylaxis in non-valvular atrial fibrillation (NVAF), utilization of oral anticoagulants (OAC) in NVAF has changed. Contemporary shifting from a VKA to a NOAC (dabigatran, rivaroxaban, or apixaban) has not been quantified, and could help assess whether these drugs are used according to recommendations.. Using Danish nationwide registries, we identified all VKA-experienced NVAF patients initiating a NOAC from 22 August 2011 to 31 December 2015 (shifters) and all VKA-experienced NVAF patients who were not switched to NOACs (non-shifters). Baseline characteristics and temporal utilization trends were examined. We included 62 065 patients with NVAF; of these, 19 386 (29.6%) shifted from a VKA to a NOAC (9973 (54.2%) shifted to dabigatran, 4775 (26.0%) to rivaroxaban, and 3638 (19.8%) to apixaban). Shifting was associated with lower age [odds ratio (OR) 0.95, 95% confidence interval (95% CI) 0.94-0.96 per 5 year increments], female gender (OR 1.33, 95% CI 1.28-1.38), and certain co-morbidities: more often stroke, bleeding, heart failure, and alcohol abuse, and less often hypertension, ischaemic heart disease, and diabetes. Shifting was common and initially dominated by shifting from VKA to dabigatran, but at the end of 2015, most shifters were shifted to rivaroxaban (45%) or apixaban (45%) whereas shifting to dabigatran decreased (to 10%).. In a contemporary setting among VKA-experienced NVAF patients; VKA is still prevalent although about 30% by December 2015 had shifted to a NOAC.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Denmark; Drug Substitution; Female; Hemorrhage; Humans; Male; Pyrazoles; Pyridones; Registries; Rivaroxaban; Stroke; Vitamin K

Background There is increasing evidence indicating oral factor Xa inhibitors can be used for secondary prevention of venous thromboembolism. Studies are needed to compare oral factor Xa inhibitors, low molecular weight heparins, and warfarin in the oncology population. The purpose of this study is to evaluate the recurrent venous thromboembolism incidence in oncology patients utilizing oral Xa inhibitors, low molecular weight heparins, or warfarin. Methods Using retrospectively collected data, we compared the recurrent venous thromboembolism incidence in oncology patients taking rivaroxaban/apixaban, enoxaparin, or warfarin with at least three months of follow-up. Patients were included if they had an active cancer, venous thromboembolism, and taking warfarin, enoxaparin, or rivaroxaban/apixaban. The primary endpoint was the first episode of recurrent venous thromboembolism at three months. Secondary endpoints included recurrent venous thromboembolism after six months, major bleeding, and mortality. Results Of 127 venous thromboembolism patients, 48 received rivaroxaban or apixaban, 23 received enoxaparin, and 56 received warfarin. The three most common cancer diagnoses were lung (21%), colorectal (14%), and breast (14%). There was no difference in venous thromboembolism recurrence at three months between the rivaroxaban/apixaban (0%), warfarin (3.6%), and the enoxaparin cohorts (4.4%) (p = 0.8319). Major bleeding at three months was only seen in one patient in the enoxaparin arm (4.2%). Mortality at three months was 0%, 3.6%, and 17.4% in the rivaroxaban/apixaban, warfarin, and enoxaparin cohorts, respectively. Conclusion The results of this retrospective study suggest that oral factor Xa inhibitors are potential options for cancer patients with venous thromboembolism. However, randomized, controlled trials are needed to confirm these results.

Topics: Aged; Aged, 80 and over; Anticoagulants; Enoxaparin; Factor Xa Inhibitors; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Neoplasms; Pyrazoles; Pyridones; Recurrence; Retrospective Studies; Rivaroxaban; Secondary Prevention; Venous Thromboembolism; Warfarin

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

Factor Xa (FXa) inhibitors, used for stroke prevention in atrial fibrillation and venous thromboembolism treatment and prevention, are the dominant non-Vitamin K oral anticoagulants on the market. While major bleeding may be less common with these agents compared to warfarin, it is always a risk, and little has been published on the most serious bleeding scenarios. This study describes a cohort of patients with FXa inhibitor-associated life-threatening bleeding events, their clinical characteristics, interventions and outcomes.. We performed a retrospective, 5-center review of FXa inhibitor-treated major bleeding patients. Investigators identified potential cases by cross-referencing ICD-9/10 codes for hemorrhage with medication lists. Investigators selected cases they deemed to require immediate reversal of coagulopathy, and reviewed charts for characteristics, reversal strategies and other interventions, and outcomes.. A total of 56 charts met the inclusion criteria for the retrospective cohort, including 29 (52%) gastrointestinal bleeds (GIB), 19 (34%) intracranial hemorrhages (ICH) and 8 (14%) others. Twenty-four (43%) patients received various factor or plasma products, and the remainder received supportive care. Thirty-day mortality was 21% (n=12). Re-anticoagulation within 30-days occurred in 23 (41%) patients. Thromboembolic events (TEEs) occurred in 6 (11%) patients. No differences were observed in outcomes by treatment strategy.. This cohort of FXa inhibitor-associated major bleeding scenarios deemed appropriate for acute anticoagulant reversal illustrates the variable approaches in the absence of a specific reversal agent.

Topics: Aged; Blood Coagulation Factors; Factor Xa Inhibitors; Female; Gastrointestinal Hemorrhage; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Intracranial Hemorrhages; Male; Plasma; Platelet Transfusion; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban

Comparative data of non-vitamin K antagonist oral anticoagulants (NOAC) are lacking in patients with atrial fibrillation (AF).. We compared effectiveness and safety of standard and reduced dose NOAC in AF patients.. Using Danish nationwide registries, we included all oral anticoagulant-naïve AF patients who initiated NOAC treatment (2012-2016). Outcome-specific and mortality-specific multiple Cox regressions were combined to compute average treatment effects as 1-year standardized differences in stroke and bleeding risks (g-formula).. Amongst 31 522 AF patients, the distribution of NOAC/dose was as follows: dabigatran standard dose (22.4%), dabigatran-reduced dose (14.0%), rivaroxaban standard dose (21.8%), rivaroxaban reduced dose (6.7%), apixaban standard dose (22.9%), and apixaban reduced dose (12.2%). The 1-year standardized absolute risks of stroke/thromboembolism were 1.73-1.98% and 2.51-2.78% with standard and reduced NOAC dose, respectively, without statistically significant differences between NOACs for given dose level. Comparing standard doses, the 1-year standardized absolute risk (95% CI) for major bleeding was for rivaroxaban 2.78% (2.42-3.17%); corresponding absolute risk differences (95% CI) were for dabigatran -0.93% (-1.45% to -0.38%) and apixaban, -0.54% (-0.99% to -0.05%). The results for major bleeding were similar for reduced NOAC dose. The 1-year standardized absolute risk (95% CI) for intracranial bleeding was for standard dose dabigatran 0.19% (0.22-0.50%); corresponding absolute risk differences (95% CI) were for rivaroxaban 0.23% (0.06-0.41%) and apixaban, 0.18% (0.01-0.34%).. Standard and reduced dose NOACs, respectively, showed no significant risk difference for associated stroke/thromboembolism. Rivaroxaban was associated with higher bleeding risk compared with dabigatran and apixaban and dabigatran was associated with lower intracranial bleeding risk compared with rivaroxaban and apixaban.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Cohort Studies; Dabigatran; Denmark; Dose-Response Relationship, Drug; Female; Hemorrhage; Humans; Male; Pyrazoles; Pyridones; Registries; Rivaroxaban; Stroke

Unanticipated drug-laboratory interactions may occur between direct oral anticoagulants (DOACs) and anti-factor Xa (AXA) levels used to monitor parenteral heparin infusions. Characterization of the extent and duration of DOAC effect on AXA levels may reduce complications with transition to heparin infusions.. To evaluate the impact of oral factor Xa inhibitors on AXA levels with and without concurrent heparin.. This retrospective descriptive study was approved by institutional review board waiver and included patients with AXA levels drawn on a heparin calibrated assay who had received a factor Xa inhibitor. Participants were divided on the basis of whether AXA levels were drawn with concurrent parenteral heparin. If transitioned to heparin, number of AXA draws required until AXA level was within therapeutic range was recorded.. A total of 50 patients (60% rivaroxaban, 40% apixaban) met inclusion criteria. When AXA levels were drawn within 12 hours of apixaban without concurrent heparin (n = 7), 71% were greater than 1 IU/mL, and 29% were below suggested trough levels (0.7-1.1 IU/mL). For AXA levels drawn within 24 hours of rivaroxaban without concurrent heparin (n = 11), 55% were greater than 1 IU/mL, 9% were within suggested trough (0.6-1 IU/mL), and 36% were below 0.6 IU/mL. In patients (n = 28) who were initiated on heparin infusion prior to AXA monitoring, administration of the DOAC within the prior 72 hours resulted in supratherapeutic initial AXA levels 69% of the time.. DOACs may cause elevations in heparin-calibrated AXA assays; this creates problematic challenges in using the AXA level to optimize heparin management.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Blood Coagulation Tests; Factor Xa Inhibitors; Female; Heparin; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban

Once-daily dosing of non-vitamin K antagonist oral anticoagulants (NOACs) may increase patient adherence to treatment but may also be associated with a higher risk of bleeding. In this study, we investigated the adherence to once- or twice-daily dosing of NOACs and the risk of bleeding in nonvalvular atrial fibrillation (NVAF) patients. This multicenter cross-sectional study, conducted between 1 September 2015 and 28 February 2016, included 2214 patients receiving NOACs for at least 3 months, due to NVAF. Patients receiving once-daily or twice-daily NOAC doses were 1:1 propensity score matched for baseline demographic characteristics and the presence of other diseases. The medication adherence was assessed by the 8-item Morisky Medication Adherence Scale. Risk factors were investigated in relation to minor and major bleeding. The mean age of patients was 71 ± 10 years, and 53% of the patients were women. The medication adherence was lower in patients receiving twice-daily NOAC doses compared to once-daily-dose group (47% versus 53%, p = 0.001), and there was no difference between the groups in terms of minor (15% versus 16%, p = 0.292) and major bleeding (3% versus 3%, p = 0.796). Independent risk factors for bleeding were non-adherence to medication (OR: 1.62, 95% CI: 1.23-2.14, p = 0.001), presence of 3 or more other diseases (OR: 10.3, 95% CI: 5.3-20.3, p < 0.001), and HAS-BLED (Hypertension, Abnormal renal and liver function, Stroke, Bleeding, Labile INR, Elderly, Drugs or alcohol) score (OR: 4.84, 95% CI: 4.04-5.8, p < 0.001). In summary, the once-daily dose of NOACs was associated with increased patient adherence to medication, while it was not associated with bleeding complications.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Cross-Sectional Studies; Dabigatran; Female; Hemorrhage; Humans; Male; Medication Adherence; Middle Aged; Patient Safety; Pyrazoles; Pyridones; Retrospective Studies; Risk Factors; Rivaroxaban; Stroke; Turkey

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

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

Cancer is a known hypercoagulable state that leads to an increased risk of venous thromboembolism (VTE). Low molecular weight heparin remains the preferred anticoagulant for VTE in patients with cancer over vitamin K antagonist. However, the preferred anticoagulant in prevention of stroke and systemic embolism in atrial fibrillation (AF) in patients with cancer has yet to be determined. The direct oral anticoagulants (DOACs) are increasingly being utilized; however their role in cancer has only recently been investigated. The objective of this retrospective cohort was to describe real-world anticoagulation prescribing patterns in cancer patients at a large academic medical center between January 1, 2013 and October 31, 2016. We sought to assess the safety, tolerability, and efficacy of DOACs in patients with cancer for either VTE and/or AF. Patient demographic, clinical characteristics, as well as bleeding and thrombotic events were collected. There were 214 patients in our analysis, of which 71 patients (33%) received a DOAC [apixaban (n = 22), dabigatran (n = 17), and rivaroxaban (n = 32)]. There were fewer bleeding events and/or discontinuations in the DOAC group compared to enoxaparin (13 vs. 27, p = 0.022). There was no difference in major or minor bleeds or thromboembolic events in comparing DOAC to enoxaparin or DOAC to warfarin. This was a retrospective, single-institution study assessing the safety and efficacy of DOACs compared to warfarin or enoxaparin in patients with cancer. DOACs may represent an alternative to warfarin or enoxaparin in patients with cancer for VTE and/or stroke reduction in AF.

Topics: Adult; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Enoxaparin; Hemorrhage; Humans; Middle Aged; Neoplasms; Practice Patterns, Physicians'; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Thrombosis; Treatment Outcome; Venous Thromboembolism; Warfarin

The objective of this project was to compare the time from initiation of oral anticoagulation to hospital discharge between warfarin and direct oral anticoagulants (DOACs) for the treatment of acute venous thromboembolism (VTE). This retrospective observational study was done at a single VA medical center. A total of 107 patients were included, with 42 patients (39%) in the DOAC group, which included rivaroxaban, dabigatran, and apixaban, and 65 patients (61%) in the warfarin group. Variables collected through chart review included comorbid conditions, time from initiation of oral anticoagulation to discharge, emergency department (ED) visits and readmission within 30 or 90 days, and bleeding events. The DOAC group had a shorter time to discharge compared to the warfarin group (28 vs. 114 h, p < 0.001). There were similar 30 and 90-day hospital readmission rates and/or ED visits for DOACs (23.8 and 33.3%) compared to warfarin (18.5 and 30.8%), including those related to bleeding of any severity (11.9% for DOACs vs. 9.2% for warfarin; p = 0.75). There was one major bleeding event in the DOAC group and two in the warfarin group. The use of DOACs for the treatment of acute VTE in hospitalized patients was associated with shorter time to hospital discharge when compared to warfarin.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Dabigatran; Female; Hemorrhage; Humans; Length of Stay; Male; Middle Aged; Patient Readmission; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Venous Thromboembolism; Warfarin

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

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

The development of non-vitamin K-dependent oral anticoagulants (NOACs) is a new alternative to treatment with warfarin. The purpose of this study was to explore drug prescription decisions of NOACs or warfarin from hospital physicians in cardiovascular departments.. A qualitative study with focus group interviews was conducted in three different hospitals. The interview guide explored the background of prescribing anticoagulants (warfarin, dabigatran, rivaroxaban, and apixaban) and experiences with effect and side-effects they had observed in patients.. The systematic text condensation eluded four main themes: when to prescribe NOACs, concern about side-effects, pharmaceutical properties and patient adherence, and prescribing policy and intra-professional communication. All available anticoagulants were prescribed. However, no specific NOAC was preferred. Factors perceived as contraindications for NOACs varied among the doctors. Most had observed side-effects of NOACs; however, these rarely influenced prescribing decisions due to small differences in safety profiles. Few drug-drug interactions and fixed daily doses made NOACs easy to prescribe; but some doctors had experienced lack of drug effect for some patients. Non-adherence with NOACs was harder to spot. Some different prescribing cultures had evolved between the different hospitals and between general practitioners.. The hospital physicians chose anticoagulants based on patient conditions as renal function, bleeding risks, and drug interactions being the most common taken into account. They could not say which NOAC was best, and wish that future studies could compare the different NOACs, and not just compare with warfarin.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Cardiovascular Diseases; Clinical Decision-Making; Dabigatran; Drug Monitoring; Drug Resistance; Factor Xa Inhibitors; Focus Groups; General Practitioners; Hemorrhage; Humans; Medical Staff, Hospital; Medication Adherence; Norway; Practice Patterns, Physicians'; Pyrazoles; Pyridones; Qualitative Research; Risk; Rivaroxaban; Warfarin

Direct-acting oral anticoagulants (DOACs), which have gained approval for stroke prevention in nonvalvular atrial fibrillation and treatment of venous thromboembolism, have become increasingly preferred over warfarin given their predictable pharmacodynamics, lack of required monitoring, and superior outcomes. Direct-acting oral anticoagulants have been shown to be associated with an increased frequency of gastrointestinal bleeding compared with warfarin, but the severity and characteristics of gastrointestinal bleeding in these patients is poorly understood.. We retrospectively evaluated electronic medical records of patients with gastrointestinal bleeding (n = 8496) from 2010-2016. We identified 61 patients with gastrointestinal bleeding episodes while treated with DOACs (rivaroxaban, dabigatran, or apixaban) and 123 patients with gastrointestinal bleeding while taking warfarin. We randomly selected a control group of 296 patients with gastrointestinal bleeding who were not receiving anticoagulation treatment from the same sample. Outcomes included the need for hospitalization, blood transfusion, endoscopic or surgical intervention, and 30-day mortality.. The DOAC and warfarin groups were similar in terms of age and underlying comorbidity (assessed using the Charlson Comorbidity Index), but the DOAC group had greater concomitant aspirin use. Gastrointestinal bleeding was classified as upper (n = 186), lower (n = 88), anorectal (n = 183), small bowel (n = 9), and indeterminate (n = 14). After adjusting for differences in baseline variables, the DOAC group had fewer hospitalizations and required fewer transfusions than the warfarin group. The DOAC and control groups were not statistically different for all outcomes. There were no significant mortality differences among groups.. Although prior studies have shown a higher frequency of gastrointestinal bleeding in patients treated with DOACs compared with warfarin, our data suggest that gastrointestinal bleeding in patients taking DOACs may be less severe. These differences occurred despite significantly greater concomitant aspirin use in the DOAC group compared with warfarin users.

Topics: Administration, Oral; Aged; Anticoagulants; Arteriovenous Malformations; Aspirin; Blood Transfusion; Case-Control Studies; Dabigatran; Diverticulum; Endoscopy, Gastrointestinal; Female; Gastrointestinal Hemorrhage; Hemorrhoids; Hospitalization; Humans; Male; Middle Aged; Peptic Ulcer; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Warfarin

To describe the prevalence and associated factors of inappropriate doses of direct oral anticoagulants (DOAC) in a national registry of patients of real clinical practice.. Five hundred and thirty outpatients with atrial fibrillation treated with DOAC were included in a prospective, national, multicentre study. The appropriateness of the doses of DOAC was defined according to the recommendations of the European Heart Rhythm Association. Mean age was 73 ± 9 years, with a 46% of women. Two hundred and sixty-seven patients were prescribed dabigatran, 190 rivaroxaban, and 73 apixaban. A total of 172 patients (32%) did not receive the appropriate dose: 93 patients received a lower dose (18%) and 79 patients a higher dose (15%). In the comparisons among the subgroups of inappropriately low, appropriate, and inappropriately high dose, we observed significant trends to older age (69 ± 8 years vs. 73 ± 10 years vs. 77 ± 6 years), more frequent female sex (37% vs. 46% vs. 59%), antiplatelet drugs (5% vs. 8% vs. 25%), rivaroxaban (14% vs. 38% vs. 53%), and apixaban use (5% vs. 15% vs. 19%), higher CHAD2DS2-VASc (3.00 ± 1.38 vs. 3.58 ± 1.67 vs. 4.59 ± 1.44) and HAS-BLED scores (1.83 ± 0.87 vs. 1.92 ± 1.07 vs. 2.47 ± 1.13), lower body mass index (30 ± 6 kg/m2 vs. 29 ± 4 kg/m2 vs. 28 ± 4 kg/m2) and glomerular filtration rate (74 ± 27 mL/min vs. 70 ± 22 mL/min vs. 63 ± 16 mL/min), and lower frequency of dabigatran use (81% vs. 47% vs. 28%) (all comparisons P ≤ 0.01).. In this real-life study, 32% of patients received an inappropriate dose of DOAC. Several clinical factors can identify patients at risk of this situation.

Topics: Aged; Aged, 80 and over; Antithrombins; Atrial Fibrillation; Comorbidity; Dabigatran; Factor Xa Inhibitors; Female; Guideline Adherence; Humans; Inappropriate Prescribing; Logistic Models; Male; Middle Aged; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Registries; Retrospective Studies; Rivaroxaban; Stroke; Thromboembolism

To assess the outcome of direct oral anticoagulants (DOACs), specifically Xa inhibitors: rivaroxaban and apixaban, for the treatment of venous thromboembolism (VTE) of atypical location (VTE-AL), portal, mesenteric, hepatic, splenic, gonadal, renal, and cerebral veins, prospectively collected data of Mayo Thrombophilia Clinic Registry were used.. Patients with acute VTE-AL treated with DOACs, enrolled between March 1, 2013, and February 1, 2017, were compared with patients with VTE of typical location (VTE-TL: deep vein thrombosis of extremities and/or pulmonary embolism) receiving DOACs and with patients with VTE-AL treated with enoxaparin.. Out of 623 patients with acute VTE receiving the study drug within 14 days of diagnosis, there were 63 with VTE-AL: 36 on DOAC, 23 on enoxaparin, and 4 on warfarin; 352 received DOAC for VTE-TL. The VTE-AL treated with DOAC/enoxaparin included the following: splanchnic (26/22), ovarian (8/2), renal (3/5), and cerebral veins (1/1), respectively. Recurrence rate (per 100 person-years) for the VTE-AL group receiving DOAC was 7.3, which was not different when compared with those for VTE-TL (2.4; P=.13) and VTE-AL groups receiving enoxaparin (23.7; P=.37). Major bleeding rate in the VTE-AL group receiving DOAC was not different compared with those for VTE-TL (7.2 vs 3.0; P=.26) and VTE-AL groups on enoxaparin (22.4; P=.31). Mortality was higher in the VTE-AL group on DOAC compared with the VTE-TL group (21.45 [95% CI, 7.87-46.69] vs 8.26 [95% CI, 5.35, 12.20]; P=.03). All patients with VTE-AL with events had cancer.. The VTE recurrence and bleeding rates for rivaroxaban and apixaban used in VTE-AL are not different from those in patients with VTE-TL and similar to that for enoxaparin.

Topics: Aged; Anticoagulants; Drug-Related Side Effects and Adverse Reactions; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban; Venous Thromboembolism

To evaluate inpatient oral anticoagulant (OAC) treatment, discharge location, and post-discharge OAC treatment for patients hospitalized with non-valvular atrial fibrillation (NVAF).. Retrospective study using claims data linked to hospital electronic health records (EHR). Patients (n = 2,484) were hospitalized with a primary (38%) or secondary (62%) diagnosis of AF without evidence of mitral valvular heart disease or valve replacement between January 2009 and September 2013. Inpatient OAC treatment was identified from EHR data.. Inpatient and post-discharge OAC treatment [direct OAC (DOAC; apixaban, rivaroxaban, dabigatran), warfarin, no OAC] and discharge location (long-term care, home health-care, home self-care).. Mean age was 72.6 years, 61.2% were male, and 89.5% had a CHA2DS2-VASc score ≥2. Overall, 6.4% received a DOAC, 38.0% warfarin, and 55.6% no OAC during hospitalization. Compared to other treatment groups, patients receiving DOAC were younger and more likely to be male. The majority (72.2%) were discharged to home health-care, 13.2% home self-care, and 6.0% long-term care. Among patients who were treated with warfarin during hospitalization, 40.3% filled a warfarin prescription within 30 days post-discharge, whereas among patients who were treated with a DOAC, 52.4% filled a DOAC prescription within 30 days post-discharge. Some NVAF patients not treated with an OAC during hospitalization filled a prescription for warfarin (18.0%) or DOAC (1.9%) within 30 days post-discharge. Results were similar among patients with CHA2DS2-VASc score ≥2.. Most patients hospitalized for NVAF were discharged to home support, and the majority did not have OAC treatment during hospitalization or the 30 days post-discharge. Additional investigation should be conducted on trends beyond 30 days post-hospitalization, and the reasons for not receiving anticoagulation therapy in patients at moderate-to-severe risk of stroke or systemic embolism. Helping to avoid preventable strokes is an important goal for public health.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Embolism; Female; Hospitalization; Humans; Inpatients; Male; Middle Aged; Outpatients; Patient Discharge; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Warfarin

Since 2010, four oral anticoagulants have been approved for marketing in addition to warfarin for treatment of thromboembolic disease. Limited head-to-head data exist comparing these treatments, leaving patients and clinicians with little guidance for selecting a strategy that balances recurrence reduction with bleeding risk. In the dabigatran, apixaban, rivaroxban, edoxaban and warfarin comparative effectiveness research study, we compare all five currently available oral anticoagulant agents for the extended treatment of deep venous thrombosis and pulmonary embolism, as well as no extended treatment, and evaluate whether results differ in specific sub-populations. As our population includes Medicare novel anticoagulant users and large numbers of commercially insured and Medicaid patients, our results will likely be transportable to the majority of US patients experiencing a DVT or pulmonary embolism.. NCT03271450.

Topics: Anticoagulants; Antithrombins; Comparative Effectiveness Research; Dabigatran; Factor Xa Inhibitors; Humans; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Research Design; Rivaroxaban; Thiazoles; Venous Thrombosis; Warfarin

Since non-vitamin K antagonist oral anticoagulants (NOACs) were released for clinical use, many studies have investigated its effectiveness in stroke prevention. In this study, to determine whether or not there is a difference in outcome in secondary stroke prevention between warfarin and NOACs, patients with embolic stroke with newly prescribed anticoagulants were prospectively analyzed.. Patients with acute ischemic stroke, who newly started anticoagulant therapy, were consecutively asked to participate in this study. Enrolled patients (76.3 ± 11.0 years old) were classified into warfarin (n = 48), dabigatran (n = 73), rivaroxaban (n = 49), and apixaban (n = 65). The outcome in 1 year was prospectively investigated at outpatient clinic or telephone interview. Recurrence of stroke and death was considered as the critical incidence.. The prevalence of risk factors was not different among all medicines. Patients with dabigatran showed significantly younger onset age (P < .001: 72.2 years old) and milder neurologic deficits than patients on other medicines (P < .001). Cumulative incident rates were 7.1%, 15.3%, 19.0%, and 29.7% for dabigatran, apixaban, rivaroxaban, and warfarin, respectively. Dabigatran showed relatively better outcome compared with warfarin (P = .069) and rivaroxaban (P = .055). All patients on NOACs presented lower cumulative stroke recurrence compared with warfarin.. Even in the situation of secondary stroke prevention, noninferiority of NOACs to warfarin might be demonstrated.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Brain Ischemia; Dabigatran; Female; Humans; Incidence; Kaplan-Meier Estimate; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Pyrazoles; Pyridones; Recurrence; Risk Factors; Rivaroxaban; Secondary Prevention; Stroke; Time Factors; Treatment Outcome; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Dabigatran; Databases, Factual; Drug Synergism; Hemorrhage; Humans; Pyrazoles; Pyridones; Retrospective Studies; Risk; Rivaroxaban; Taiwan

Topics: Aged; Anticoagulants; Antithrombins; Blood Coagulation; Blood Coagulation Factors; Dabigatran; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Punctures; Pyrazoles; Pyridones; Rivaroxaban; Vascular System Injuries; Warfarin

The study was performed to analyze the results of open-heart surgery and bleeding complications after administration of novel oral anticoagulants (NOAC).. We investigated 81 consecutive patients (median age 74 years, interquartile range [IQR]: 68 to 78) who underwent open-heart operations at our institution between July 2014 and June 2016. All patients presented for surgery while on NOAC therapy: 37 received rivaroxaban (45.7%), 35 apixaban (43.2%), and 9 dabigatran (11.1%). The calculated risk using the European System for Cardiac Operative Risk Evaluation II was 3.5% (IQR: 2.0% to 8.1%).. Surgery was performed at a median 4 days (IQR: 3 to 6) after NOAC withdrawal. Reduced renal function was predictive for length of intensive care unit stay and administration of red blood cells (p < 0.0001 and p = 0.0291, respectively). The NOAC withdrawal interval significantly influenced postoperative drainage volume (p = 0.0056). Five patients needed rethoracotomy because of relevant bleeding (6.2%), 4 after apixaban (11.4%) and 1 after rivaroxaban therapy (2.7%). Apixaban showed a borderline influence on prolonged intensive care unit stay (p = 0.0736). Prolonged cardiopulmonary bypass time was predictive for thrombocyte administration (p = 0.0249). Intensive care unit stay was 2 days after NOAC withdrawal of 10 days, compared with 4.2 days without termination. Thirty-day mortality was 3.7%.. A lengthy NOAC withdrawal period, particularly for patients with reduced renal function, is essential for safe open-heart surgery. We conclude that despite official recommendations, patients should whenever possible not be considered for elective cardiac surgery within 10 days of terminating NOAC treatment.

Topics: Aged; Anticoagulants; Blood Transfusion; Cardiac Surgical Procedures; Critical Care; Dabigatran; Female; Heart Diseases; Humans; Length of Stay; Male; Postoperative Hemorrhage; Pyrazoles; Pyridones; Retrospective Studies; Risk Assessment; Rivaroxaban

Topics: Administration, Oral; Anticoagulants; Dabigatran; Emergency Treatment; Humans; Partial Thromboplastin Time; Pyrazoles; Pyridones; Reference Values; Rivaroxaban; Sensitivity and Specificity; Thrombin Time

Essentials Tests for direct oral anticoagulants (DOACs) are not widely applied. These tests are perceived to be difficult to run and subjected to large between-lab variation. We carried out proficiency testing surveys for DOAC testing in Italy. Interlab variability was small and similar to that of the international normalised ratio.. Background Tests for direct oral anticoagulants (DOACs) are not widely available. The perception that they are difficult to perform and are subject to large between-laboratory variation makes their implementation difficult. Aims We carried out proficiency-testing surveys for DOACs within the activity of the external quality-assessment scheme of the Italian Federation of Thrombosis Centers. Design Participants were provided with coded freeze-dried plasmas without or with graded concentrations of the three main DOACs, and asked to measure prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time and DOAC concentrations with dedicated tests. The results were centralized for statistical analysis. Results and conclusions All participants (n = 235) reported results for PT and APTT, and approximately one-third reported results for DOAC concentration. PT and APTT showed variable responsiveness to DOACs: PT was more responsive to rivaroxaban than to dabigatran or apixaban. APTT was more responsive to dabigatran than to rivaroxaban or apixaban. The thrombin time ratio (test/normal) was close to unity for plasmas without dabigatran, and was high (i.e. 7.6-fold or 15.4-fold longer than the plasma free from the drug) for plasmas containing dabigatran at low (i.e. 42 ng mL

Topics: Administration, Oral; Anticoagulants; Antithrombins; Blood Coagulation Tests; Calibration; Clinical Laboratory Services; Dabigatran; Humans; International Normalized Ratio; Italy; Partial Thromboplastin Time; Prothrombin Time; Pyrazoles; Pyridones; Quality Control; Reproducibility of Results; Rivaroxaban; Surveys and Questionnaires; Thrombin Time

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Comorbidity; Dabigatran; Female; Hemorrhage; Humans; Male; Middle Aged; Patient Safety; Phenprocoumon; Proportional Hazards Models; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Treatment Outcome

Antithrombin (AT) activity tests are used for diagnosing hereditary AT deficiency, a main genetic determinant of thrombophilia. They are either based on inhibition of thrombin (FIIa) or activated factor X (FXa). FXa-based assays have been suggested to be preferable to FIIa-based assays due to their higher sensitivity for certain AT deficiency causing mutations. To assess the performance of these two methods in a real-world scenario, 745 consecutively collected samples from patients referred to our institute during a 3-month period for thrombophilia testing were analysed. In samples from patients not receiving direct-acting oral anticoagulants or heparins (

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Antithrombin III; Antithrombins; Blood Coagulation; Blood Coagulation Tests; Child; Child, Preschool; Dose-Response Relationship, Drug; Factor Xa; Factor Xa Inhibitors; Female; Heparin; Heparin, Low-Molecular-Weight; Humans; Infant; Male; Middle Aged; Mutation; Pyrazoles; Pyridones; Rivaroxaban; Thrombin; Thrombophilia; Young Adult

Topics: Anticoagulants; Antithrombins; Clinical Trials as Topic; Dabigatran; Hemorrhage; Pulmonary Embolism; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Survival Analysis; Venous Thrombosis; Warfarin

Direct oral coagulants (DOAC) have been shown to decrease the frequency of intracerebral hemorrhage (ICH) compared with warfarin. However, the precise characteristics, such as the size and locations of the hemorrhage, and outcome and onset time of ICH in patient taking DOAC are not fully elucidated.. We retrospectively analyzed the characteristics of symptomatic patients with ICH taking either DOAC or warfarin between January 2012 and December 2015.. Out of 400 consecutive patients with ICH, 15 patients were DOAC-ICH and 24 patients were warfarin-ICH. DOAC-ICH was observed in 6 patients with 10 mg of rivaroxaban, 5 patients with 15 mg of rivaroxaban, and 1 patient with 10 mg of apixaban, 5 mg of apixaban, 30 mg of edoxaban, and 60 mg of edoxaban. Prothrombin time was well controlled in most of the warfarin-ICH patients (83.3%). The locations of ICH were similar in both groups; however, median ICH volume was significantly smaller in DOAC-ICH patients than in warfarin-ICH patients (P < .01) and ICH around basal ganglia seemed to show great difference between the groups. DOAC-ICH patients showed better neurological outcome at the time of discharge than warfarin patients (P < .01), and the ratio of good prognosis was significantly higher in the DOAC-ICH patients than in the warfarin-ICH patients (P < .01). The onset of warfarin-ICH was frequently observed in the morning and evening, whereas DOAC-ICH did not show any specific onset time.. Patients with DOAC-ICH showed smaller ICH volume and better clinical outcomes than patients with warfarin-ICH, and DOAC-ICH did not show any specific onset peak.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Circadian Rhythm; Female; Humans; Male; Middle Aged; Prothrombin Time; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Risk Factors; Rivaroxaban; Thiazoles; Time Factors; Treatment Outcome; Warfarin

Oral anticoagulants are prescribed in non-valvular atrial fibrillation for stroke prevention; however, little is known about the current management of anticoagulation in France, particularly given the availability of non-vitamin K antagonist oral anticoagulants in recent years.. To describe the characteristics of patients prescribed oral anticoagulants, and assess treatment persistence in French primary care.. We conducted a cohort study of patients with non-valvular atrial fibrillation, who were newly prescribed oral anticoagulants between 1 January 2014 and 31 January 2016, using French primary care data (IMS Longitudinal Patient Database). Adjusting for baseline characteristics, risk of non-persistence (switch or discontinuation) was compared using Cox regression.. Of 4111 patients, 1710 were newly prescribed vitamin K antagonists, 1257 rivaroxaban, 744 apixaban and 400 dabigatran. The median age was 76 years, and 57.5% were male. History of hypertension was the most common co-morbidity (68.1%). Compared with vitamin K antagonists, non-persistence was higher with rivaroxaban (hazard ratio: 1.28; 95% confidence interval: 1.13-1.45) and dabigatran (hazard ratio: 1.42; 95% confidence interval: 1.20-1.69) and similar with apixaban (hazard ratio: 1.12; 95% confidence interval: 0.96-1.32).. Non-persistence (treatment discontinuation or switch) with vitamin K antagonists was lower than with rivaroxaban and dabigatran in French primary care; however, non-persistence with the newest drug, apixaban, was similar to vitamin K antagonists. Larger studies with longer follow-up are needed to support these findings. This study is registered on ClinicalTrials.gov (NCT02488421).

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Comorbidity; Dabigatran; Databases, Factual; Drug Prescriptions; Drug Substitution; Female; France; Humans; Male; Primary Health Care; Proportional Hazards Models; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Stroke; Time Factors; Treatment Outcome

The effect of direct oral anticoagulants (DOACs) on turbidimetric measurements of plasma clot formation and susceptibility to fibrinolysis may facilitate a comparison between different classes of anticoagulants in plasma samples. We obtained 424 citrate plasma samples from 226 atrial fibrillation patients on anticoagulation and 24 samples without anticoagulation serving as controls. As comparators, we measured the international normalized ratio (INR) for phenprocoumon samples (N = 166), anti-Xa for low molecular weight heparin (LMWH) samples (N = 42), and DOAC levels with mass spectrometry (dabigatran N = 40, rivaroxaban N = 110, apixaban N = 42). Plasma clot formation and lysis were recorded continuously on a photometer after addition of an activation mix (tissue factor 2 pmol/l and tissue plasminogen activator 333 ng/ml). We used linear regression and ANCOVA for correlation analysis. Clot formation lag phase was prolonged in the presence of anticoagulants in a concentration-dependent manner for DOACs (dabigatran Spearman r = 0.74; rivaroxaban r = 0.78; apixaban r = 0.72, all p < 0.0001), INR dependent for phenprocoumon (r = 0.59, p < 0.0001), anti-Xa level dependent in LMWH samples (r = 0.90, p < 0.0001). Maximum rate of clot formation and peak clot turbidity were reduced in the presence of anticoagulants, but correlated only moderately with the comparator measures of anticoagulation. The clot lysis time was inversely correlated with DOAC concentrations in the presence of recombinant thrombomodulin. A direct ex vivo comparison between the effects of different classes of anticoagulants is possible with turbidimetric measurement of plasma clot formation and lysis. Anticoagulation inhibited clot formation in a plasma concentration manner for DOACs, INR dependent for phenprocoumon, and anti-Xa dependent for LMWH. Susceptibility to fibrinolysis increased with increasing DOAC concentrations.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Case-Control Studies; Dabigatran; Factor Xa Inhibitors; Female; Fibrin Clot Lysis Time; Heparin, Low-Molecular-Weight; Humans; Linear Models; Male; Middle Aged; Phenprocoumon; Plasma; Pyrazoles; Pyridones; Rivaroxaban; Thromboplastin; Tissue Plasminogen Activator

Clinical practice guidelines recommend regular kidney function monitoring in atrial fibrillation patients on nonvitamin K oral anticoagulants (NOAC); however, information regarding compliance with these recommendations in daily life conditions is scarce. We sought to determine the compliance with kidney function monitoring recommendations in nonvalvular atrial fibrillation (NVAF) patients starting NOAC and its implication on the appropriateness of NOAC dosage.. This study involves the retrospective analysis of a multicentre registry including consecutive NVAF patients who started NOAC (n = 692). Drug dosage changes and serum creatinine determinations were recorded during 1-year follow-up. European Heart Rhythm Association criteria were used to define the appropriateness of kidney function monitoring as well as adequate NOAC dosage.. During the follow-up (334 ± 89 days), the compliance with kidney function monitoring recommendations was 61% (n = 425). After multivariate adjustment, age (OR × year: 0.92 (CI 95%: 0.89-0.95) P < .001), creatinine clearance (OR × mL/min: 1.02 (CI 95%: 1.01-1.03) P < .001) and adequate NOAC dosage at baseline (OR: 1.54 (CI 95%: 1.06-2.23), P = .024) were independent predictors of appropriate kidney function monitoring. Compliance with kidney function monitoring recommendations was independently associated with change to appropriate NOAC dose after 1 year (OR: 2.80 (CI 95%: 1.01-7.80), P = .049).. Noncompliance with kidney function monitoring recommendations is common in NVAF patients starting NOAC, especially in elderly patients with kidney dysfunction. Compliance with kidney function monitoring recommendations was associated with adequate NOAC dosage at 1-year follow-up. Further studies are warranted to evaluate the implication of kidney function monitoring on prognosis.

Topics: Age Factors; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Creatinine; Dabigatran; Drug Monitoring; Factor Xa Inhibitors; Female; Guideline Adherence; Humans; Kidney Function Tests; Male; Multivariate Analysis; Odds Ratio; Practice Guidelines as Topic; Pyrazoles; Pyridones; Registries; Renal Insufficiency; Retrospective Studies; Rivaroxaban; Stroke

This guidance document was prepared on behalf of the International Council for Standardization in Haematology (ICSH) for providing haemostasis-related guidance documents for clinical laboratories. This inaugural coagulation ICSH document was developed by an ad hoc committee, comprised of international clinical and laboratory direct acting oral anticoagulant (DOAC) experts. The committee developed consensus recommendations for laboratory measurement of DOACs (dabigatran, rivaroxaban, apixaban and edoxaban), which would be germane for laboratories assessing DOAC anticoagulation. This guidance document addresses all phases of laboratory DOAC measurements, including pre-analytical (e.g. preferred time sample collection, preferred sample type, sample stability), analytical (gold standard method, screening and quantifying methods) and post analytical (e.g. reporting units, quality assurance). The committee addressed the use and limitations of screening tests such as prothrombin time, activated partial thromboplastin time as well as viscoelastic measurements of clotting blood and point of care methods. Additionally, the committee provided recommendations for the proper validation or verification of performance of laboratory assays prior to implementation for clinical use, and external quality assurance to provide continuous assessment of testing and reporting method.

Topics: Administration, Oral; Anticoagulants; Chromatography; Clinical Laboratory Techniques; Dabigatran; Hematology; Humans; International Cooperation; Mass Spectrometry; Partial Thromboplastin Time; Point-of-Care Testing; Prothrombin; Prothrombin Time; Pyrazoles; Pyridines; Pyridones; Quality Assurance, Health Care; Rivaroxaban; Thiazoles

Prevention of thromboembolic complications is a priority in patients with atrial fibrillation (AF). The use of non-vitamin K antagonist oral anticoagulants (NOACs) is more common and some patients have indications for a reduced dose.. We sought to evaluate the frequency of NOACs being prescribed to AF patients and to compare the groups of AF patients receiving standard and reduced doses.. The study included 1327 patients diagnosed with AF and hospitalised at an institution of the highest referral level in cardiology in the years 2015-2016. Final analysis encompassed 713 patients with nonvalvular AF, who were prescribed NOACs upon discharge.. In the group of patients receiving NOACs, standard doses were used in 383 (53.7%) patients, while 330 (46.3%) patients received reduced doses. Among patients treated with reduced doses, dabigatran was prescribed to 186 (56.4%) patients, rivaroxaban to 124 (37.5%) patients, and apixaban to 20 (6.1%) patients. Absence of indications for dose reduction was identified in 54 out of 330 (16.4%) patients receiving reduced-dose NOACs, including six out of 20 patients receiving reduced-dose apixaban (30%), 21 out of 186 patients receiving reduced-dose dabigatran (11.3%), and 24 out of 124 pa-tients receiving reduced-dose rivaroxaban (19.3%). Among patients treated with reduced dose of dabigatran (n = 186), one indication for dose reduction was observed in 75 patients, and at least two indications were observed in 90 patients. One indication was observed in 71 patients, and at least two indications were observed in 30 patients treated with a reduced dose of rivaroxaban (n = 124).. Standard doses of NOACs were prescribed to most hospitalised AF patients. Apixaban was prescribed more frequently in the reduced-dose regimen, while the frequencies of standard and reduced doses prescribed were similar for dabigatran and rivaroxaban. Absence of indications for dose reduction as defined in relevant guidelines and Summaries of Product Characteristics was identified in 15.5% of patients receiving reduced doses of NOACs. More than one indication for dose reduction was identified in most patients receiving reduced-dose dabigatran, while one indication was identified in most patients receiving reduced-dose rivaroxaban.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antithrombins; Atrial Fibrillation; Dabigatran; Female; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban; Stroke

The purpose of this study was to evaluate whether anticoagulation (warfarin or direct oral inhibitors) affected the success of endovenous treatment.. Patients taking anticoagulation (warfarin or direct oral inhibitors) undergoing endovenous treatment in the form of endovenous laser ablation (EVLA) were matched against controls for sex, age, leg, and vein. Data were collected prospectively between January 2012 and March 2017. The primary endpoint was failure of treatment at 6-week postoperative duplex scan. The rates of major bleeding, hematoma, endothermal heat-induced thrombosis, venous thromboembolism, or pulmonary embolism were also compared between groups.. Two hundred eighty-four limbs underwent EVLA during the study period. Of this, 23/284 (8.1%) procedures were done in patients on anticoagulation. 21/23 (91.3%) limbs had venous occlusion at follow-up compared with 23/23 (100%) of controls ( P = .49). The patient who failed treatment in the anticoagulation group had undergone small saphenous vein (SSV) ablation. There was no difference in the complication rates between groups.. This study demonstrates that anticoagulation does not affect success rates of EVLA though there was higher recanalization rate in patients undergoing SSV ablation. Anticoagulation can be continued safely in patients undergoing this procedure.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation; Endovascular Procedures; Factor Xa Inhibitors; Female; Humans; Laser Therapy; Male; Middle Aged; Postoperative Complications; Pyrazoles; Pyridones; Retrospective Studies; Risk Factors; Rivaroxaban; Saphenous Vein; Time Factors; Treatment Outcome; Venous Insufficiency; Warfarin

Topics: Biopsy; Drug Substitution; Factor Xa Inhibitors; Glomerulonephritis, IGA; Humans; IgA Vasculitis; Male; Middle Aged; Pulmonary Embolism; Pyrazoles; Pyridones; Rivaroxaban; Treatment Outcome; Venous Thrombosis

Essentials Direct oral anticoagulants (DOACs) do not require laboratory monitoring currently. DOAC specific measurements were performed at trough in patients with atrial fibrillation. Patients who developed thromboembolic events showed lower DOAC plasma levels. This study supports the concept of measuring DOAC levels at steady state.. Background Direct oral anticoagulants (DOACs) are administered at fixed doses without the need for dose adjustment according to laboratory testing. High interindividual variability in drug blood levels has been shown with all DOACs. To evaluate a possible relationship between DOAC C-trough anticoagulant levels and thromboembolic events, 565 consecutive naive patients with atrial fibrillation (AF) were enrolled in this study performed within the START Laboratory Registry. Methods DOAC-specific measurements (diluted thrombin time or anti-activated factor II calibrated for dabigatran; anti-activated FX calibrated for rivaroxaban or apixaban) at C-trough were performed locally at steady state within 15-25 days after the start of treatment. For each DOAC, the interval of C-trough levels, from the limit of quantification to the highest value, was subdivided into four equal classes, and results were attributed to these classes; the median values of results were also calculated. Thromboembolic complications occurring during 1 year of follow-up were recorded. Results Thromboembolic events (1.8%) occurred in 10 patients who had baseline C-trough levels in the lowest class of drug levels. The incidence of thromboembolic events among patients with DOAC C-trough levels in the lowest level class was 2.4%, and that in the remaining groups was 0%. The patients with thrombotic complications also had a higher mean CHA

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antithrombins; Atrial Fibrillation; Blood Coagulation Tests; Dabigatran; Drug Monitoring; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Predictive Value of Tests; Preliminary Data; Pyrazoles; Pyridones; Registries; Risk Assessment; Risk Factors; Rivaroxaban; Thromboembolism; Time Factors; Treatment Outcome

: The number of patients with nonvalvular atrial fibrillation (NV-AF) who require long-term anticoagulation and also have a higher risk of bleeding is increasing. Recently, there is no information regarding real on-treatment anti-Xa activity in patients with NV-AF and a higher risk of bleeding who receive oral factor Xa inhibitors. The aim of this study was to determine trough and peak anti-Xa activity in these patients. This single-centre pilot study enrolled 41 patients with NV-AF and a higher risk of bleeding defined as Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly score at least 3 points. Twenty-one patients were treated with rivaroxaban and 17 patients were treated with apixaban. The trough and peak samples of these patients were tested for anti-Xa activity with factor Xa-calibrated anti-Xa chromogenic analysis. The detected trough anti-Xa activity was 63.2 ± 44.4 ng/ml. There was a significant increase in peak anti-Xa activity up to 170.3 ± 99.6 ng/ml (P < 0.001) observed. There were no significant differences in trough (52.4 ± 41.9 vs. 76.0 ± 45.4 ng/ml; P = 0.12) and peak (187.2 ± 122.5 vs. 151.5 ± 64.0 ng/ml; P = 0.27) anti-Xa activity between rivaroxaban-treated and apixaban-treated patients. This study demonstrated the anti-Xa activity in oral factor Xa inhibitor-treated patients with NV-AF and a higher risk of bleeding. No significant differences in this activity between rivaroxaban-treated and apixaban-treated patients were found.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Factor Xa; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Pilot Projects; Pyrazoles; Pyridones; Risk; Rivaroxaban

Oral factor Xa inhibitors are increasingly used for anticoagulation, but there is no approved reversal agent. Prothrombin complex concentrate (PCC) for the management of Xa-inhibitor-associated bleeding has been described in small case series and one cohort study. Patients on apixaban or rivaroxaban, suffering a major bleed, were treated at nine Canadian hospitals as per existing hospital protocol with a fixed dose of PCC 2,000 units and subsequently recruited for a 30-day follow-up. The treating physician evaluated the haemostatic effectiveness as observed during the first day as good, moderate or poor/none, using an assessment guide. Safety outcomes were thromboembolism or death. We recruited 66 patients with major bleeding who were treated with PCC and who were receiving rivaroxaban (56%) or apixaban (44%). The effectiveness was assessed as good in 65% (95% confidence interval [CI], 53-77), moderate in 20% (95% CI, 10-30) and poor/none in 15% (95% CI, 6-24). For the 36 patients with intracranial haemorrhage, the corresponding ratings were 67, 17 and 17%, and for 16 patients with gastrointestinal bleeding they were 69, 12 and 19%, respectively. There were nine deaths (14%) by 30 days, and five (8%) major thromboembolic events. In a

Topics: Administration, Oral; Aged; Aged, 80 and over; Blood Coagulation Factors; Canada; Coagulants; Factor Xa Inhibitors; Female; Gastrointestinal Hemorrhage; Hemostasis; Humans; Intracranial Hemorrhages; Male; Prospective Studies; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Thromboembolism; Time Factors; Treatment Outcome

Because of their lower bleeding risk and simplicity of use, direct oral anticoagulants (DOACs) could represent an interesting alternative to conventional anticoagulant treatment with vitamin K antagonists for patients with pulmonary arterial hypertension (PAH). P-glycoprotein (P-gp) plays a key role in DOAC pharmacokinetics. Type 5-phosphodiesterase inhibitors (PDE5is), a drug class commonly used in the treatment of PAH, have been shown to strongly inhibit P-gp. This work aimed to assess potential P-gp-mediated drug-drug interactions between PDE5is and DOACs using in vitro methods. A cellular model of drug transport assay, using P-gp-overexpressing Madin-Darby canine kidney cells (transfected with the human P-gp gene), was used to determine the bidirectional permeabilities of two DOACs (rivaroxaban and apixaban) in the absence and presence of increasing concentrations (0.5-100

Topics: Administration, Oral; Animals; Anticoagulants; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Dogs; Drug Interactions; Inhibitory Concentration 50; Madin Darby Canine Kidney Cells; Phosphodiesterase 5 Inhibitors; Pyrazoles; Pyridones; Rivaroxaban; Tissue Distribution

Direct oral anticoagulants (DOACs) are prescribed for anticoagulation in patients with atrial fibrillation and venous thromboembolic disease. Fixed doses are recommended, but measuring their serum drug concentrations as a basis for dose adjustments may be useful in some clinical settings.. An ultra-high-performance liquid chromatography-tandem mass spectrometry method for the analysis of the DOACs apixaban, dabigatran, edoxaban, and rivaroxaban in human serum was developed and validated. A 100-µL serum sample was handled using a pipetting robot. Protein precipitation was performed with 375 µL of 1% formic acid in acetonitrile (vol/vol), and phospholipid removal was performed using a Waters Ostro 96-well plate. The injection volume was 1 µL, and run time was 3.0 minutes.. The calibration range was 5-800 nmol/L. The between-day precision relative SDs were in the range of 3.3%-10%. Recoveries ranged from 85% to 105%, and matrix effects from 88% to 102%, when corrected with internal standard. Edoxaban was, in contrast to the other DOACs, unstable when stored for more than 6 hours at 30°C. The suitability of the method was demonstrated by analyzing routine samples from 345 patients undergoing anticoagulation treatment.. The developed method fulfilled the set validation criteria, and its suitability was demonstrated in a routine setting. The instability of edoxaban may complicate the transport of routine samples to the laboratory.

Topics: Antithrombins; Chromatography, High Pressure Liquid; Chromatography, Liquid; Dabigatran; Factor Xa Inhibitors; Humans; Pyrazoles; Pyridines; Pyridones; Reproducibility of Results; Rivaroxaban; Tandem Mass Spectrometry; Thiazoles

There is limited evidence on patients' adherence and the impact of the prescribed dosing regimen in non-vitamin-K oral anticoagulants (NOACs). We aimed to assess secondary adherence to NOACs and to determine the impact of the dosing regimen in patients with atrial fibrillation.. Patients using a NOAC between 2009 and 2013 were identified from the nation-wide Swedish Prescribed Drug Register and the Dutch regional IADB.nl database. Patients using a consistent dosage for at least 180 consecutive days were included. Adherence was calculated using the medication possession ratio (MPR) and adjusted for overlapping dates. Adherence was defined as a MPR ≥0.8. Sensitivity analyses were performed using a MPR ≥0.9. Logistic regression was performed to compare secondary adherence and to explore the influence of the dosing regimen.. A total of 5254 Swedish and 430 Dutch NOAC users were included. The mean MPR was 96.0% (SD 7.8%) in Sweden and 95.1% (SD 10.1%) in the Netherlands. Multivariable logistic regression analysis showed that a twice daily regimen had a lower likelihood of being secondary adherent compared to a once daily regimen in Sweden (odds ratio [OR] 0.21 [95% CI 0.12-0.35]).. The influence of selection bias introduced by the inclusion criterion of ≥2 dispensations covering at least 180 days could not be excluded.. This study demonstrated that secondary adherence was high in this specific setting among patients with at least two initial dispensations of a NOAC covering a minimum of 180 days. The use of NOACs in a once daily regimen showed higher adherence compared to a twice daily regimen.

Topics: Administration, Oral; Aged; Antithrombins; Atrial Fibrillation; Dabigatran; Dose-Response Relationship, Drug; Drug Utilization Review; Female; Humans; Male; Medication Adherence; Middle Aged; Netherlands; Pyrazoles; Pyridones; Rivaroxaban; Sweden; Thromboembolism

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

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

Left atrial thrombus (LAT) and dense spontaneous echocardiographic contrast (SEC) detected by transesophageal echocardiography (TEE) in patients on continuous direct oral anticoagulants (DOAC) therapy before catheter ablation of atrial fibrillation (AF) or atrial flutter (AFL) have been described.. We sought to compare rates of TEE-detected LAT and dense SEC among patients taking different DOACs.. We evaluated 609 consecutive patients from 3 tertiary hospitals (median age 65 years; interquartile range 58-71 years; 436 (72%) men) who were on ≥4 weeks of continuous DOAC therapy (dabigatran, n = 166 [27%]; rivaroxaban, n = 257 [42%]; or apixaban, n = 186 [31%]) undergoing TEE before catheter ablation of AF/AFL. Demographic, clinical, and TEE data were collected for each patient.. Despite ≥4 weeks of continuous DOAC therapy, 17 patients (2.8%) had LAT and 15 patients (2.5%) had dense SEC detected by TEE. The rates of LAT were 3.0%, 3.5%, and 1.6% for patients on dabigatran, rivaroxaban, and apixaban, respectively (P = .482). The rates of dense SEC were 1.2%, 3.5%, and 2.2% for patients on dabigatran, rivaroxaban, and apixaban, respectively (P = .299). Congestive heart failure (odds ratio 4.4; 95% confidence interval 1.6-12; P = .003) and moderate/severe left atrial enlargement (odds ratio 3.1; 95% confidence interval 1.1-8.6; P = .026) were independent predictors of LAT.. In this study, ∼3% of patients on continuous DOAC therapy had LAT detected before catheter ablation of AF/AFL. Specific DOAC therapy did not significantly affect the rates of LAT detection.

Topics: Administration, Oral; Aged; Antithrombins; Atrial Fibrillation; Catheter Ablation; Contrast Media; Dabigatran; Dose-Response Relationship, Drug; Echocardiography, Transesophageal; Factor Xa Inhibitors; Female; Heart Atria; Heart Diseases; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Thrombosis

Non-valvular atrial fibrillation (NVAF) is common in older adults. Oral anticoagulation is indicated to reduce the risk of stroke and systemic embolism, but it also poses a risk of bleeding, particularly in the elderly. Direct oral anticoagulants (DOACs) provide an alternative to warfarin and their use in the treatment of AF is growing. We conducted a retrospective cohort study to assess the quality of DOAC prescribing in elderly patients with NVAF in a large academic health system and to compare practice with consensus best practice recommendations. We searched the electronic medical record for patients ≥ 65 years of age who were newly initiated on a DOAC for AF from January 2013 through December 2015. Patient and provider characteristics, baseline laboratory investigations, concomitant medications, and interval to first follow-up were recorded. 192 patients met eligibility criteria. The most commonly prescribed DOACs were rivaroxaban (65%) and apixaban (26%). Despite consensus recommendations that patients have a baseline creatinine, complete blood cell count, and coagulation studies prior to DOAC initiation, these tests were not performed in 18, 31, and 67% of patients, respectively. Consensus recommendations also suggest a follow-up visit within 1 month of DOAC initiation. However, only 39% of patients had a return visit within 6 weeks and 43% did not have follow-up within 12 weeks. DOAC prescribing in elderly patients with NVAF frequently fell short of quality standards. Interventions to enhance the quality of DOAC prescribing in this high-risk population are needed.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Female; Humans; Male; Practice Guidelines as Topic; Practice Patterns, Physicians'; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban

Medication non-adherence can result in poor health outcomes. Understanding differences in adherence rates to non-vitamin K oral anticoagulants (NOACs) could guide treatment decisions and improve clinical outcomes among patients with non-valvular atrial fibrillation (NVAF).. To compare adherence to rivaroxaban and apixaban among the overall NVAF population and subgroups of prior oral anticoagulant (OAC) users (e.g., multiple comorbidities, non-adherence risk factors).. Using healthcare claims from the Truven Health Analytics MarketScan (7/2012-7/2015), adult patients with ≥2 dispensings of rivaroxaban or apixaban ≥ 180 days apart with > 60 days of supply, ≥ 6 months of pre- and post-index eligibility, ≥ 1 atrial fibrillation diagnosis pre- or on the index date, and without valvular involvement were identified. Propensity-score methods adjusting for potential baseline confounders were used to create matched cohorts of rivaroxaban and apixaban patients. Adherence was assessed during the implementation phase using the percentage of patients with proportion of days covered (PDC) ≥0.8 at 6 months. Subgroups of patients with prior OAC use were evaluated; additional subgroups were identified and evaluated by Quan-Charlson Comorbidity index ≥2 and presence of non-adherence risk factors (i.e., mental disorders, stress, isolation, and rheumatoid arthritis).. A total of 13,890 NVAF subjects were included in each of the 2 matched cohorts. All baseline characteristics were balanced between cohorts. At 6 months, significantly more rivaroxaban users were adherent to treatment compared to apixaban users (81.8% vs. 78.0%; absolute difference of 3.8%; p<.001). Rivaroxaban users had significantly higher adherence rates in all subgroups examined.. Rivaroxaban users had consistently higher adherence rates than apixaban users overall and among all NVAF subgroups examined.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Female; Humans; Male; Medication Adherence; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban

Whether non-vitamin K antagonist oral anticoagulants (NOACs) are superior to warfarin among Asians with nonvalvular atrial fibrillation remains unclear.. In this nationwide retrospective cohort study collected from Taiwan National Health Insurance Research Database, there were 5843, 20 079, 27 777, and 19 375 nonvalvular atrial fibrillation patients taking apixaban, dabigatran, rivaroxaban and warfarin, respectively, from June 1, 2012 to December 31, 2016. Propensity-score weighting was used to balance covariates across study groups. Patients were followed until the first occurrence of any efficacy or safety outcome or the end date of study. Hazard ratios (95% confidence intervals) comparing apixaban, dabigatran, and rivaroxaban with warfarin were: ischemic stroke/systemic embolism (IS/SE), 0.55 (0.43-0.69), 0.82 (0.68-0.98), and 0.81 (0.67-0.97); major bleeding, 0.41 (0.31-0.53), 0.65 (0.53-0.80), and 0.58 (0.46-0.72); and all-cause mortality, 0.58 (0.51-0.66), 0.61 (0.54-0.68), and 0.57 (0.51-0.65). A total of 3623 (62%), 17 760 (88%), and 26 000 (94%) patients were taking low-dose apixaban (2.5 mg twice daily), dabigatran (110 mg twice daily), and rivaroxaban (10-15 mg once daily), respectively. Similar to all-dose NOACs, all low-dose NOACs had lower risk of IS/SE, major bleeding, and mortality when compared with warfarin. In contrast to other standard-dose NOACs, apixaban was associated with lower risks of IS/SE (0.45 [0.31-0.65]), major bleeding (0.29 [0.18-0.46]), and mortality (0.23 [0.17-0.31]) than warfarin.. All NOACs were associated with lower risk of IS/SE, major bleeding, and mortality compared with warfarin in the largest real-world practice among Asians with nonvalvular atrial fibrillation. All low-dose NOACs had lower risk of IS/SE, major bleeding, and mortality when compared with warfarin. Standard-dose apixaban caused a lower risk of IS/SE, major bleeding, and mortality compared with warfarin.

Topics: Aged; Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Dose-Response Relationship, Drug; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Humans; Incidence; Male; Propensity Score; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Taiwan; Thromboembolism; Treatment Outcome; Warfarin

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

Frailty predicts poorer outcomes and decreased anticoagulation use in patients with nonvalvular atrial fibrillation. We sought to assess the effectiveness and safety of apixaban, dabigatran and rivaroxaban versus warfarin in frail nonvalvular atrial fibrillation patients.. Using US MarketScan claims data from November 2011 to December 2016, we identified frail oral anticoagulant-naïve nonvalvular atrial fibrillation patients with ≥12 months of continuous insurance coverage before oral anticoagulant initiation. Frailty status was determined using the Johns Hopkins Claims-based Frailty Indicator score (≥0.20 indicating frailty). Users of apixaban, dabigatran, or rivaroxaban were separately 1:1 matched to warfarin users via propensity-scores, with residual absolute standardized differences <0.1 being achieved for all covariates after matching. Patients were followed for up to 2 years or until an event, insurance disenrollment or end of follow-up. Rates of stroke or systemic embolism and major bleeding were compared using Cox regression and reported as hazard ratios (HRs) and 95% confidence intervals (CIs). In total, 2700, 2784, and 5270 patients were included in the apixaban, dabigatran, and rivaroxaban 1:1 matched analyses to warfarin. At 2 years, neither apixaban nor dabigatran were associated with differences in the hazard of stroke or systemic embolism (HR=0.78; 95% CI=0.46-1.35 and HR=0.94; 0.60-1.45) or major bleeding (HR=0.72; 95% CI=0.49-1.06 and HR=0.87; 95% CI=0.63-1.19) versus warfarin. Rivaroxaban was associated with reduced stroke or systemic embolism at 2 years (HR=0.68; 95% CI=0.49-0.95) without significantly altering major bleeding risk (HR=1.07; 95% CI=0.81-1.32).. Our study found rivaroxaban but not apixaban or dabigatran to be associated with reduced SSE versus warfarin in frail nonvalvular atrial fibrillation patients. No direct-acting oral anticoagulants demonstrated a significant difference in major bleeding versus warfarin.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Dose-Response Relationship, Drug; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Follow-Up Studies; Frail Elderly; Humans; Incidence; Male; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Time Factors; Treatment Outcome; United States; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Cohort Studies; Dabigatran; Humans; Pyrazoles; Pyridones; Rivaroxaban; Stroke

To identify differences in clinical characteristics and severity of cerebral small vessel disease (CSVD) including cerebral microbleeds (CMBs), between patients suffering ischemic stroke (IS) or intracerebral hemorrhage (ICH) while taking novel (non-vitamin K antagonists) oral anticoagulants (NOACs).. Multicenter, prospective, observational cohort study performed at 38 centers between 2012 and 2015. We compared demographics, comorbidity, and functional status (before and after stroke) between NOAC-IS and NOAC-ICH patients. Extent of white matter lesions (WML), and location and counts of CMBs were analyzed in a subgroup of patients for whom MRI including hemorrhage-sensitive sequences was available.. A total of 351 patients were included (290 NOAC-IS, 61 NOAC-ICH). Functional status was worse in NOAC-ICH patients before and after stroke. No significant differences were found for demographic variables and cardiovascular comorbidity. In the subgroup with available MRI (n = 116), the proportion of patients with at least one CMB was higher in NOAC-ICH than in NOAC-IS (15/19 [79%] vs 36/97 [37%], P < .001), as was the absolute number of CMBs (median 5 [IQR 1-24] vs 0 [0-1], P < .001). WML were more extensive in NOAC-ICH than in NOAC-IS patients. Adjusted for WML, logistic regression analysis showed higher odds of NOAC-ICH in patients with CMB than without (OR 5.60 [1.64-19.14], P = .006).. Patients with NOAC-ICH have similar clinical characteristics but a higher prevalent burden of CSVD compared to NOAC-IS. The role of neuroimaging in selection of patients for anticoagulation with NOAC requires further investigation in longitudinal studies.

Topics: Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Cerebral Small Vessel Diseases; Comorbidity; Dabigatran; Female; Humans; Magnetic Resonance Imaging; Male; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thrombolytic Therapy

The objective of the study was to examine how the comparative effectiveness and safety of direct oral anticoagulants (DOACs) and warfarin differ across subgroups of patients with atrial fibrillation defined by stroke risk (CHA2DS2-VASc score ≤3, 4 to 5, ≥6). Using Medicare claims data, we identified patients newly diagnosed with atrial fibrillation in 2013 to 2014 who initiated warfarin (n=12,354), apixaban (n=2,358), dabigatran (n=1,415), or rivaroxaban (n=5,139), and categorized them according to their CHA2DS2-VASc score (≤3, 4 to 5, ≥6). Primary outcomes included the combined risk of ischemic stroke, other thromboembolic event and death, and the risk of bleeding. We constructed Cox proportional hazard models that included terms for treatment, CHA2DS2-VASc subgroup, and the interaction between them, and controlled for demographics and a comprehensive list of clinical characteristics. We found that DOACs were generally more effective than warfarin, but this effect was most pronounced in the lowest risk subgroup. Specifically, the hazard ratio for the primary effectiveness outcome with apixaban compared with warfarin was 0.46 (95% confidence interval [CI] 0.32 to 0.65) for CHA2DS2-VASc ≤3, 0.71 (95% CI 0.61 to 0.86) for 4 to 5, and 0.86 (95% CI 0.74 to 1.01) for ≥6 (p value for interaction = 0.005). The comparative safety profile of DOACs versus warfarin did not change with CHA2DS2-VASc score. In conclusion, DOACs are more effective than warfarin, but this effect is more pronounced in patients with lower risk of stroke. Further research is needed to validate these findings in other patient cohorts and uncover their underlying mechanisms.

Topics: Administration, Oral; Aged; Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Dose-Response Relationship, Drug; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Follow-Up Studies; Humans; Incidence; Male; Pyrazoles; Pyridones; Retrospective Studies; Risk Assessment; Risk Factors; Rivaroxaban; Stroke; Survival Rate; Treatment Outcome; United States; Warfarin

Discontinuation of oral anticoagulants may expose non-valvular atrial fibrillation (NVAF) patients to an increased risk of stroke. This study describes the real-world discontinuation rates and compared the risk of drug discontinuation among NVAF patients initiating apixaban, warfarin, dabigatran, or rivaroxaban. This retrospective cohort study evaluated newly-anticoagulated NVAF patients in the MarketScan® data population from 01/01/2012 through 12/31/2014. Discontinuation was defined as a lack of subsequent prescription of the index drug within 30 days after the last supply day of the last prescription. A Cox model was used to estimate the hazard ratio (HR) of discontinuation, adjusted for age, sex, and comorbidities. Among 45,361 eligible NVAF patients, 15,461 (34.1%) initiated warfarin; 7,438 (16.4%) apixaban; 4,661 (10.3%) dabigatran; and 17,801 (39.2%) initiated rivaroxaban treatment. Compared to warfarin, patients who initiated dabigatran (adjusted HR [aHR]: 0.84, 95% confidence interval [CI]: 0.80-0.87, P<0.001), rivaroxaban (aHR: 0.70, 95% CI: 0.68-0.73, P<0.001), or apixaban (aHR: 0.57, 95% CI: 0.55-0.60, P<0.001) were 16%, 30%, and 43% less likely to discontinue treatment, respectively. When compared to apixaban, patients who initiated dabigatran (aHR: 1.46, 95% CI: 1.38-1.54, P<0.001) or rivaroxaban (aHR: 1.23, 95% CI: 1.17-1.28, P<0.001) were more likely to discontinue treatment. Among newly-anticoagulated NVAF patients in the real-world setting, initiation on rivaroxaban, dabigatran, or apixaban was associated with a significantly lower risk of discontinuation compared to warfarin. When compared to apixaban, patients who initiated treatment with warfarin, dabigatran, or rivaroxaban were more likely to discontinue treatment.

Topics: Adolescent; Adult; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Hemorrhage; Humans; Incidence; Male; Middle Aged; Prognosis; Pyrazoles; Pyridones; Retrospective Studies; Risk Factors; Rivaroxaban; Stroke; United States; Warfarin; Withholding Treatment; Young Adult

Warfarin and new oral anticoagulants are effective in reducing stroke in atrial fibrillation; however, the benefits and risks rates in clinical trials show heterogeneity for each anticoagulant, and is unknown the cost influence on a model considering most of the treatment consequences. We designed a benefit-risk and cost assessment of oral anticoagulants.. We followed the roadmap proposed by IMI-PROTECT and the considerations of emerged good practice to perform Multi-Criteria Decision Analysis (MCDA). The roadmap defines the following steps: (1) planning, (2) evidence gathering and data preparation, (3) analyses, (4) explorations, and (5) conclusions. We defined two reference points (0-100) to allocate numerical values for scores and weights, and used an analogue numeric scale to assess physicians' preferences. As benefits of the anticoagulant therapy, we included reductions in stroke and all-cause mortality; intracranial haemorrhage, gastrointestinal haemorrhage, minor bleeding and myocardial infarction were considered risks. We also made an estimation of the annual drug cost per person.. The scores were: Apixaban 33, Dabigatrán 25, warfarin 18 and Rivaroxaban 14 this score reveals the most preferred up to the less preferred option, considering the benefit-risk ratio and drug costs altogether. The relative model weights were: 51.1% for risks, 40.4% for benefits and 8.5% for cost. The sensitivity analysis confirms the model robustness.. From this analysis, apixaban should be considered as the preferred anticoagulant option -due to a better benefit-risk balance and a minor cost influence- followed by dabigatran, warfarin and rivaroxaban.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Cost-Benefit Analysis; Dabigatran; Decision Support Techniques; Drug Costs; Hemorrhage; Humans; Models, Statistical; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Stroke; Warfarin

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

There is a general lack of studies evaluating medication adherence with self-report scales for elderly patients in treatment with direct oral anticoagulants (DOACs). The aim of the study was to assess the degree of adherence to DOAC therapy in a population of elderly outpatients aged 65 years or older affected by non-valvular atrial fibrillation (NVAF), using the 4-item Morisky Medication Adherence Scale, and to identify potential factors, including the geriatric multidimensional evaluation, which can affect adherence in the study population. A total of 103 subjects, anticoagulated with DOACs for NVAF in primary or secondary prevention, were eligible; 76 showed adequate adhesion to anticoagulant therapy, while 27 showed inadequate adherence. Participants underwent biochemical assessment and Morisky Scale, Instrumental Activities of Daily Living, CHA2DS2-VASc, HAS-BLED, mental status and nutritional evaluations were performed. 2% of subjects assumed Dabigatran at low dose, while 7.8% at standard dose, 9.7% assumed low-dose of Rivaroxaban and 30.1% at standard dose, 6.8% assumed Apixaban at low dose and 39.7% at standard dose, and finally 1% assumed Edoxaban at low dose and 2.9% at standard dose. Most subjects took the DOACs without help (80.6%), while 16 subjects were helped by a family member (15.5%) and 4 were assisted by a caregiver (3.9%). Binary logistic regression considered inappropriate adherence as a dependent variable, while age, male sex, polypharmacotherapy, cognitive decay, caregiver help for therapy assumption, duration of DOAC therapy and double daily administration were considered as independent variables. The double daily administration was an independent factor, determining inappropriate adherence with an OR of 2.88 (p = 0.048, CI 1.003-8.286).

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Caregivers; Dabigatran; Female; Humans; Male; Medication Adherence; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Self Report; Thiazoles

Topics: Blood Coagulation; Factor Xa Inhibitors; Female; Humans; Male; Pyrazoles; Pyridones; Rivaroxaban

The management of major bleeding in patients treated with direct oral anticoagulants (DOACs) is still not well established. START-Events, a branch of the START registry (Survey on anTicoagulated pAtients RegisTer) (NCT02219984), aims to describe the actual management of bleeding or recurrent thrombotic events in routine clinical practice. We here present the results of the management of bleeding patients. The START-Event registry is a prospective, observational, multicenter, international study. Baseline characteristics (demographic, clinical, risk factors) of patients, laboratory data at admission and during follow-up, site of bleeding, therapeutic strategies, and outcomes at the time of hospital discharge and after 6 months were recorded on a web-based case report form. Between January 2015 and December 2016, 117 patients with major bleeding events were enrolled. Non-valvular atrial fibrillation (NVAF) was the indication for treatment in 84% (62% males); 53 patients had intracranial bleeding (13 fatal), 42 had gastrointestinal bleeding (1 fatal), and 22 had bleeding in other sites. Therapeutic interventions for the management of bleeding were performed in 71% of patients. Therapeutic strategies with/without surgery or invasive procedures included: fluid replacement or red blood cells transfusion, prothrombin complex concentrates (3 or 4 factors), antifibrinolytic drugs, and the administration of idarucizumab. Creatinine, blood cell count, and PT/aPTT were the most frequent tests requested, while specific DOAC measurements were performed in 23% of patients. Mortality during hospitalization was 11.9%, at 6-month follow-up 15.5%. Our data confirm a high heterogeneity in the management of bleeding complications in patients treated with DOACs.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Blood Coagulation Factors; Dabigatran; Female; Hemorrhage; Humans; Male; Prospective Studies; Pyrazoles; Pyridones; Registries; Rivaroxaban; Treatment Outcome; Ventricular Fibrillation

New oral anticoagulants are non-inferior compared with warfarin regarding stroke prevention in atrial fibrillation, with similar or decreased risk of bleeding. However, it is unclear whether high TTR warfarin is as effective and safe as NOACs. Our objective was to investigate efficacy and safety of apixaban, dabigatran or rivaroxaban compared with warfarin in clinical practice.. Nationwide retrospective cohort study based on Swedish quality registries. Atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban or warfarin between 2013-01-01 and 2015-12-31 were included. Main outcome measures were all-cause stroke and systemic embolism, all-cause stroke, ischemic stroke, hemorrhagic stroke; major bleeding, intracranial bleeding, gastrointestinal bleeding, other bleeding (fatal or requiring hospital care); all-cause mortality; myocardial infarction.. The study included 64,382 patients corresponding to 81,176 treatment years. Of these, 37,174 patients were instituted on warfarin, 6574 on dabigatran, 8323 on rivaroxaban and 12,311 on apixaban. In warfarin treated patients, the time in therapeutic range was 71.4%. After propensity score matching, there was no significant difference in risk of stroke or systemic embolism between NOAC and warfarin treated patients. Hazard ratios for major bleeding events were 0.63(95%CI 0.52-0.75) for apixaban, 0.74(0.62-0.87) for dabigatran and 1.06(0.92-1.23) for rivaroxaban, compared with warfarin.. This study showed no difference between apixaban, dabigatran, or rivaroxaban compared to high TTR warfarin treatment regarding stroke prevention. However, fewer bleeding events were seen for apixaban and dabigatran, but not for rivaroxaban. Further studies are needed on the comparability of individual NOACs with respect to bleeding risks.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Humans; Male; Pyrazoles; Pyridones; Rivaroxaban; Warfarin

Direct oral anticoagulants (DOAC) are at least non-inferior to warfarin in efficacy and safety among patients with nonvalvular atrial fibrillation. Limited evidence is available regarding outcomes for nonvalvular atrial fibrillation patients with coronary/peripheral artery disease.. Non-valvular atrial fibrillation patients aged ≥65 years diagnosed with coronary/peripheral artery disease in the US Medicare population, newly initiating DOACs (apixaban, rivaroxaban, dabigatran) or warfarin were selected from January 1, 2013 to September 30, 2015. Propensity score matching was used to compare DOACs vs warfarin. Cox proportional hazards models were used to estimate the risk of stroke/systemic embolism, major bleeding, and composite of stroke/myocardial infarction/all-cause mortality.. There were 15,527 apixaban-warfarin, 6,962 dabigatran-warfarin, and 25,903 rivaroxaban-warfarin-matched pairs, with a mean follow-up of 5-6 months. Compared with warfarin, apixaban was associated with lower rates of stroke/systemic embolism (hazard ratio [HR] 0.48; 95% confidence interval [CI], 0.37-0.62), major bleeding (HR 0.66; 95% CI, 0.58-0.75), and stroke/myocardial infarction/all-cause mortality (HR 0.63; 95% CI, 0.58-0.69); dabigatran and rivaroxaban were associated with lower rates of stroke/myocardial infarction/all-cause mortality (HR 0.79; 95% CI, 0.70-0.90 and HR 0.87; 95% CI, 0.81-0.92, respectively). Rivaroxaban was associated with a lower rate of stroke/systemic embolism (HR 0.72; 95% CI, 0.60-0.89) and a higher rate of major bleeding (HR 1.14; 95% CI, 1.05-1.23) vs warfarin.. All DOACs were associated with lower stroke/myocardial infarction/all-cause mortality rates compared with warfarin; differences were observed in rates of stroke/systemic embolism and major bleeding. Findings from this observational analysis provide important insights about oral anticoagulation therapy among non-valvular atrial fibrillation patients with coronary/peripheral artery disease and may help physicians in the decision-making process when treating this high-risk group of patients.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Coronary Artery Disease; Dabigatran; Embolism; Female; Hemorrhage; Humans; Male; Medicare; Myocardial Infarction; Peripheral Arterial Disease; Proportional Hazards Models; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; United States; Warfarin