edoxaban and apixaban

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In recent years, the significant limitations associated with the use of vitamin K antagonists (VKA) have encouraged the development of new agents. Based upon the central roles played by the serine proteases thrombin and Factor Xa in the blood coagulation cascade, direct thrombin inhibitors and direct Factor Xa inhibitors have been developed. These agents, which include the direct thrombin inhibitor dabigatran etexilate and the Factor Xa inhibitors rivaroxaban and idrabiotaparinux are free from many of the limitations of VKAs. According to the results of available phase III randomized clinical trials, both dabigatran and rivaroxaban are effective and safe enough to qualify as ideal oral anticoagulants for the initial and long-term treatment of patients with acute venous thromboembolism (VTE). Rivaroxaban does not require an initial parenteral treatment and can be given in once daily administrations after the first three weeks. Both of them have limitations for the treatment of patients with severe renal failure, and require further investigations in cancer patients and in pregnant patients with VTE. Both of them lack an antidote.

Topics: Anticoagulants; Antithrombins; Benzimidazoles; Biotin; Dabigatran; Humans; Oligosaccharides; Pyrazoles; Pyridines; Pyridones; Thiazoles; Venous Thromboembolism; Vitamin K

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Vitamin K antagonists, such as warfarin, have been the mainstay of oral anticoagulation for many decades. Although effective, warfarin has numerous limitations, including a variable dose requirement from patient to patient because of differences in dietary vitamin K intake, common genetic polymorphisms, and multiple drug interactions that affect its pharmacodynamics and metabolism. Consequently, warfarin requires frequent monitoring to ensure that a therapeutic anticoagulant effect has been achieved because excessive anticoagulation can lead to bleeding, and because insufficient anticoagulation can result in thrombosis. Such monitoring is burdensome for patients and physicians and is costly for the health care system. These limitations have prompted the development of new oral anticoagulants that target either factor Xa or thrombin. Although the path to the development of these drugs has been long, the new drugs are at least as effective and safe as warfarin, but they streamline clinical care because they can be administered in fixed doses without routine coagulation monitoring. This article focuses on rivaroxaban, apixaban, and edoxaban, the oral factor Xa inhibitors in the most advanced stages of development. After 20 years of discovery research, these agents are already licensed for several indications. Thus, the long path to finding replacements for warfarin has finally reached fruition. Therefore, development of the oral factor Xa inhibitors represents a translational science success story.

Topics: Animals; Anticoagulants; Drug Design; Factor Xa Inhibitors; Humans; Pyrazoles; Pyridines; Pyridones; Thiazoles; Thrombosis

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Atrial fibrillation (AF) may cause cerebral and systemic embolism. An increased D-dimer level indicates hyperactivation of secondary fibrinolysis, resulting in predilection for thrombosis. To clarify the differential effects of anticoagulation therapy, we compared the D-dimer levels in peripheral and left atrial (LA) blood of atrial fibrillation patients scheduled for ablation.. We analyzed 141 patients with non-valvular AF (dabigatran, n = 30; apixaban, n = 47; edoxaban, n = 64; mean age: 68 years, male: 60%). Peripheral venous blood and LA blood was collected before pulmonary vein isolation. We examined the laboratory and echocardiographic parameters.. After adjusting for baseline characteristics, D-dimer level in the LA was significantly higher in patients treated with edoxaban than that in those on apixaban (0.77 ± 0.05 vs. 0.60 ± 0.05 μg/mL, P = 0.047), although there were no significant differences in peripheral D-dimer levels. We classified the D-dimer value of the LA into a normal group (< 0.9) and a high value group (≥ 1.0); the peripheral prothrombin fragment F1 + 2 level (odds ratio [OR] 1.012; 95% confidence interval [CI]: 1.003-1.022; P = 0.008) and left ventricular ejection fraction (LVEF) (OR, 0.947; 95% CI, 0.910-0.986; P = 0.008) were potential predictors of high LA D-dimer levels.. In apixaban-treated patients, the D-dimer level in the left atrium was lower than in edoxaban-treated patients on the day of ablation, suggesting that the anticoagulant effect of apixaban on the left atrium is better than that of edoxaban in patients with AF.

Topics: Administration, Oral; Aged; Antithrombins; Atrial Fibrillation; Biomarkers; Dabigatran; Factor Xa Inhibitors; Female; Fibrin Fibrinogen Degradation Products; Humans; Male; Middle Aged; Prospective Studies; Pyrazoles; Pyridines; Pyridones; Thiazoles; Treatment Outcome

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

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

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

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

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

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

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

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

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

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: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Blood Specimen Collection; Dabigatran; Humans; Middle Aged; Preservation, Biological; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles

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

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

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

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

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

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

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

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

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

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

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

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

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

Topics: Administration, Oral; Alopecia; Anticoagulants; Dabigatran; Data Mining; Databases, Factual; Humans; Minoxidil; Pharmacovigilance; Platelet-Rich Plasma; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles

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: Adult; Ambulatory Care; Bed Rest; COVID-19; Factor Xa Inhibitors; Humans; Male; Middle Aged; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Risk Factors; Thiazoles; Treatment Outcome; Venous Thromboembolism; Venous Thrombosis

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

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

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

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

Convexity subarachnoid hemorrhage (cSAH) is typically due to head trauma, but it rarely occurs subsequent to acute ischemic stroke. Direct oral anticoagulants (DOACs) have favorable bleeding profiles as compared with warfarin, and, to our knowledge, no DOAC has been regarded as a causative agent for cSAH. Here, we reported 2 patients with cSAH apparently caused by starting DOAC therapy. No hemorrhage had been evident just prior to treatment initiation, but cSAH occurred so soon after DOAC therapy began. Each of our patients had occlusion or severe stenosis of a major artery due to emboligenic disease, and cSAH occurred in the territory of the affected artery. Reperfusion and dynamic changes in perfusion pressure due may trigger cSAH. Clinicians should remain alert for cSAH when starting DOAC for treatment of embolic ischemic stroke during the acute phase.

Topics: Administration, Oral; Aged; Brain Infarction; Drug Substitution; Factor Xa Inhibitors; Female; Humans; Pyrazoles; Pyridines; Pyridones; Subarachnoid Hemorrhage; Thiazoles; Time Factors

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

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

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

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

Topics: Administration, Oral; Aged; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Factor Xa Inhibitors; Female; Humans; Lower Extremity; Male; Middle Aged; Postoperative Complications; Pyrazoles; Pyridines; Pyridones; Thiazoles; Venous Thrombosis

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

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

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

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

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

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

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

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

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

Current guidelines recommend caution in prescribing concomitant use of direct-acting oral anticoagulants (DOACs) and antiepileptic drugs due to drug-drug interactions leading to potential risk of DOACs subtherapeutic concentration and treatment failure. Herein we report a significant interaction between carbamazepine (CZP) and apixaban, causing subtherapeutic concentration of the drug in a patient with atrial fibrillation who had a transient ischemic attack (TIA) episode. Another anti-Xa DOAC, edoxaban, administered to the patient after TIA occurrence did not show significant interaction with CZP. In addition to confirm that cautions should be used when antiepileptic and DOACs are concomitantly prescribed, the present case also demonstrates that, in the management of certain subsets of patients who need anticoagulant treatment, measurement of DOAC plasma concentration can help guide a personalized management and avoid adverse clinical outcomes.

Topics: Anticonvulsants; Atrial Fibrillation; Carbamazepine; Drug Interactions; Drug Monitoring; Factor Xa Inhibitors; Humans; Ischemic Attack, Transient; Precision Medicine; Pyrazoles; Pyridines; Pyridones; Thiazoles

Protein S (PS) deficiency is an inherited thrombophilia associated with an increased risk of venous thromboembolism (VTE). In Japan, unfractionated heparin followed by warfarin has been historically applied for the treatment of VTE. Recent evidence showed that direct oral anticoagulants (DOACs) were non-inferior to standard therapy with warfarin, with significantly less bleeding in patients with VTE. However, it is unknown whether DOACs are effective for the treatment of VTE in patients with thrombophilia, including protein S deficiency, due to lack of evidence. Here, we report a case of recurrent venous thrombosis during edoxaban therapy in a patient with protein S deficiency, which was successfully treated using high-dose apixaban therapy. J.Med. Invest. 66 : 182-184, February, 2019.

Topics: Administration, Oral; Aged; Anticoagulants; Humans; Male; Protein S Deficiency; Pyrazoles; Pyridines; Pyridones; Recurrence; Thiazoles; Venous Thromboembolism

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

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

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

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

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

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

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

We assessed the efficacy and safety of direct oral anticoagulants (DOACs) for the treatment of deep venous thrombosis (DVT) in the chronic phase through comparison with conventional warfarin therapy.A total of 807 consecutive patients who were diagnosed with having DVT in the chronic phase were included (484 patients to warfarin therapy and 323 patients to DOAC therapy). The condition of leg veins was assessed 3 to 6 months after starting the therapies by ultrasound examination. Major bleeding and mortality during the therapies were followed-up.There was no significant difference between the two groups in the thrombosis improvement rate (DOAC group: 91.2% versus warfarin group: 88.9%). There was no significant difference between the two groups in major bleeding (DOAC group: 1.8% versus warfarin group: 1.8%). In patients with active cancer, the DOAC group had a borderline higher thrombosis improvement rate than the warfarin group (92.1% versus 80.0%, P = 0.05). The proportion of major bleeding in the patients with active cancer was slightly higher in the warfarin group than in the DOAC group (4.3% versus 2.8%; P = 0.71). Active cancer was not an independent risk factor for major bleeding and recurrence in the DOAC group (OR 2.68, 95% CI 0.51-14.1; P = 0.24 and OR 0.65, 95% CI 0.20-2.07; P = 0.47).In treatment using oral anticoagulants for DVT in the chronic phase, DOACs exhibited equal efficacy and safety as warfarin did. Particularly DOACs appear to be an attractive therapeutic option for cancer-associated DVT in chronic phase, with relatively low anticipated rates of recurrence and major bleeding.

Topics: Administration, Oral; Aged; Anticoagulants; Antithrombins; Chronic Disease; Dabigatran; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Female; Humans; Male; Pyrazoles; Pyridines; Pyridones; Recurrence; Thiazoles; Treatment Outcome; Ultrasonography; 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

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

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

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

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

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

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

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

Oral anticoagulants used for the primary treatment of venous thromboembolism (VTE) include warfarin and the more recently introduced direct oral anticoagulants (DOACs), including rivaroxaban, apixaban, dabigatran and edoxaban. Information on the comparative safety of these medications in routine clinical practice is lacking. We identified patients with diagnoses for VTE and prescriptions for oral anticoagulants using claims data from a large U.S. insurance database from 2012 to 2017. Marginal structural logistic models were used to examine associations between type of oral anticoagulant and risk of all-cause mortality. Of 62,431 enrolees in this analysis, 51% were female and the mean age was 61.9 years. Initial oral anticoagulant prescriptions were for warfarin (

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Dabigatran; Female; Humans; Male; Middle Aged; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Risk; Rivaroxaban; Survival Analysis; Thiazoles; Venous Thromboembolism; Warfarin

Topics: Anticoagulants; Automation; Calibration; Chromatography, High Pressure Liquid; Dabigatran; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Solid Phase Extraction; Tandem Mass Spectrometry; Thiazoles

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

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

The introduction into clinical practice of direct oral anticoagulants (DOAC) has widened the scenario in the prevention and treatment of thromboembolism. However, the evaluation of the balance between the thrombotic and hemorrhagic risks is a critical issue in the choice of an oral anticoagulant agent. The availability of safety and efficacy data for each drug represents the basis to operate treatment choices. As there are no head-to-head studies comparing the different DOACs in terms of safety and efficacy, and considering the differences in registrative trial designs and characteristics of enrolled populations, several meta-analyses and real-life studies have tried to trace the safety and efficacy profiles on DOACs, but at present no definitive conclusions can be drawn due to numerous existing biases. One possible aid to help clinicians in their treatment choice is the evaluation of self-reported adverse drug reactions (ADRs) available in drug regulatory agency databases such as the Italian Medicines Agency (AIFA) pharmacovigilance database. We conducted a search in the National Pharmacovigilance Network database, available on AIFA website, in order to retrieve all the ADRs related to oral anticoagulants occurred in the period 2016-2017. We then calculated an ADR risk index (RI) for each drug, where an RI =1 indicates a balance between the percentage of ADR share and the percentage of market share for each DOAC; and an RI <1 indicates a rate of ADR lower than the rate of market share (more safe DOAC). The results showed that rivaroxaban is the DOAC with the lowest RI among the four molecules available today in Italy. Despite the limitations of this study, we believe that ADR RI can be a valuable adjunctive tool to help clinicians in their everyday clinical practice.

Topics: Administration, Oral; Adverse Drug Reaction Reporting Systems; Anticoagulants; Dabigatran; Databases, Factual; Factor Xa Inhibitors; Italy; Pharmacovigilance; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Rivaroxaban; Thiazoles

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

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

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

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

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

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

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

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

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

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

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

Topics: Anticoagulants; Antithrombins; Blood Coagulation Tests; Dabigatran; Drug Monitoring; Factor Xa Inhibitors; Humans; Partial Thromboplastin Time; Point-of-Care Testing; Prothrombin Time; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thrombin Time

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

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

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

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

Assessment of the anticoagulant activity of direct oral anticoagulants (DOACs) is justified in special clinical situations. Here, we evaluated two independent extraction methods and developed a multi-analyte ultra-high performance liquid chromatography tandem mass (UHPLC-MS/MS) method for the quantification of apixaban, dabigatran, edoxaban and rivaroxaban in human plasma.. Routine extraction based on protein precipitation with acetonitrile and subsequent centrifugation was compared to sample clean-up using commercial paramagnetic micro-particles and subsequent magnetic depletion. Stable isotope-labeled analogs of all analytes were employed as internal standards. The method was validated according to international guidelines in terms of linearity, precision, trueness, sensitivity, recovery and matrix effects. The performances of both extraction methods were assessed in clinical samples obtained from patients treated with either apixaban or rivaroxaban. Additionally, we report on a patient with nonadherence to rivaroxaban treatment and fulminant pulmonary embolism.. The method was linear from 2 to 500 ng/mL for all analytes, and quantification of DOACs was established within a run time of 2.0 min. Based on MS/MS analyte responses, relative matrix effects were better controlled for dabigatran after extraction with paramagnetic micro-particles. Internal standards fully compensated for recovery and matrix effects in all assays, yielding equivalent results for both methods. Apixaban and rivaroxaban concentrations determined in clinical samples after extraction with both methods were in good agreement (R2=0.990).. A rapid and accurate multi-component UHPLC-MS/MS method for the quantification of four DOACs in human plasma was established. Paramagnetic micro-particles appear suitable for clean-up of plasma samples for LC-MS/MS-based therapeutic drug monitoring purposes.

Topics: Blood Chemical Analysis; Chromatography, High Pressure Liquid; Dabigatran; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Tandem Mass Spectrometry; Thiazoles

Topics: Antithrombins; Dabigatran; Humans; Practice Guidelines as Topic; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Review Literature as Topic; Rivaroxaban; Thiazoles; Venous Thromboembolism; Venous Thrombosis; Vitamin K

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

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

In the Hokusai-VTE trial, 733 patients were treated with the reduced dose edoxaban regimen, which maintained efficacy and safety compared with the 60 mg dose, and was safer than warfarin. The prophylactic doses of apixaban and rivaroxaban reduced the risk of recurrent venous thromboembolism (VTE) in the extended treatment trials. Dabigatran 110 mg was approved by the European Medicine Agency for VTE treatment. Further data from registries and real-world studies will help to clarify whether patients, with other specific characteristics, can benefit from the reduced dose of direct oral anticoagulants.

Topics: Administration, Oral; Anticoagulants; Dabigatran; Dose-Response Relationship, Drug; Evidence-Based Medicine; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Venous Thromboembolism; Warfarin

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

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

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

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

Direct oral anticoagulants (DOACs) can be quantified using methods that can be performed in any clinical or research laboratory using manual or automated instrument platforms. Dabigatran etexilate, the oral direct thrombin inhibitor, can be quantified by drug-calibrated clot or chromogenic-based assays using either thrombin or ecarin as substrates. Oral direct anti-Xa inhibitors, such as rivaroxaban, apixaban, and edoxaban, can be quantified with drug-calibrated anti-Xa kits or reagents as typically used for measuring heparins (unfractionated, low molecular weight, or pentasaccharides).

Topics: Administration, Oral; Antithrombins; Blood Coagulation; Dabigatran; Drug Monitoring; Endopeptidases; Factor Xa Inhibitors; Fibrinolytic Agents; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thrombin Time; Venous Thromboembolism

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

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

The prompt assessment and the reversal of direct oral anticoagulants (DOACs) are urgent matters in the emergency care setting. Thus, we planned to elucidate the adequate prothrombin time (PT) test for the evaluation of the anticoagulant effects of various DOACs.. The anticoagulant effects of rivaroxaban, apixaban, and edoxaban were measured with 3 PT tests (Triniclot PT Excel S, Neoplastin R, and Thromborel S). Human plasma was spiked with each DOAC at a range of 0 to 1000 ng/mL, and the PT was measured using each PT test. In another series, the reversal effect of either 4-factor prothrombin complex concentrate (PCC) or activated PCC (aPCC) was evaluated with each PT test.. All PT reagents correlated with the concentrations of each DOAC, however, the reactivity was considerably different between the DOACs and the PT tests. A prolonged PT with DOACs was reversed both by PCC and aPCC in a dose-dependent manner; however, Triniclot PT Excel S showed reprolongation of the PT with a higher dose of PCC.. The proper choice of PT test is necessary for the assessments of the anticoagulant activity of DOACs. It is also important to understand the different characteristics of each PT test for the assessment of the reversal effects of PCC.

Topics: Anticoagulants; Blood Coagulation; Blood Coagulation Factors; Drug Monitoring; Humans; Prothrombin Time; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles

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

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

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

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

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

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

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

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

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

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

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

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

Topics: Administration, Oral; Anticoagulants; Dabigatran; Diet; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Warfarin

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

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

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

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

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

To establish a rapid and sensitive ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the determination of rivaroxaban, apixaban and edoxaban in rat plasma. The analytes and the internal standard (diazepam) were separated on an Acquity UPLC BEH C18 chromatography column (2.1 mm × 50 mm, 1.7 μm) using gradient elution with a mobile phase of acetonitrile and 0.1 % formic acid in water at a flow rate of 0.4 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring mode to monitor the precursor-to-product ion transitions of m/z 436.1 → 145.1 for rivaroxaban, m/z 460.0 → 443.1 for apixaban, m/z 548.2 → 366.1 for edoxaban and m/z 285.2 → 193.1 for diazepam (IS) using a positive electrospray ionization interface. The method was validated over a concentration range of 1.0-200 ng/mL for rivaroxaban, 1.0-100 ng/mL for apixaban and 1.0-500 ng/mL for edoxaban. Total time for each chromatograph was 3.5 min. The intra- and inter-day precision and accuracy of the quality control samples at low, medium, and high concentration levels exhibited relative standard deviations <10.5 % and the accuracy values ranged from -9.9 to 11.3 %. The method was successfully applied to a pharmacokinetic study of rivaroxaban, apixaban and edoxaban in rats.

Topics: Animals; Chromatography, High Pressure Liquid; Factor Xa Inhibitors; Pyrazoles; Pyridines; Pyridones; Rats; Reference Standards; Reproducibility of Results; Rivaroxaban; Tandem Mass Spectrometry; Thiazoles

This commentary focuses on the status of oral anticoagulants, namely, warfarin and the novel oral anticoagulants (NOACs) such as dabigatran, rivaroxaban, apixaban, and edoxaban.

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

The purpose of this study is to compare the effect of increasing concentrations of direct anti-Xa oral anticoagulants (DOAC) apixaban-, edoxaban-, and rivaroxaban-enriched plasma samples on various prothrombin time (PT), activated partial thromboplastin time (APTT), heparin calibrated anti-Xa methods, and other coagulation assays.. Apixaban, edoxaban, or rivaroxaban was dissolved in dimethylsulfoxide and added to pooled normal plasma to obtain concentrations ranging from 0 ng/mL to approximately 600 ng/mL. The samples were tested using Innovin(®) , Neoplastine(®) CI Plus, Recombiplastin 2G, and Thromborel(®) S for PT testing and Actin, Actin(®) FS, Actin(®) FSL, APTT-Automate, and SynthaSIL for APTT. Samples were also tested using four different anti-Xa methods calibrated for unfractionated heparin or low molecular weight heparin. Special coagulation assays included antithrombin activity, lupus anticoagulant assays, and others. For special coagulation assays, the concentration of DOAC that resulted in a >15% change from baseline value was determined. DOAC quantification was performed using liquid chromatography-tandem mass spectrometry.. All PT and APTT reagents demonstrated a higher sensitivity for edoxaban and rivaroxaban than for apixaban. Anti-Xa methods were able to detect low concentrations of DOAC. DOACs effected special coagulation assays to differing degrees, with lupus anticoagulant testing using dilute viper venom, the most sensitive test to the presence of anti-Xa DOAC.. No PT or APTT reagent system effectively detected apixaban. All anti-Xa methods demonstrated sensitivity to low concentrations of DOAC. Dilute viper venom methods are exquisitely sensitive to anti-Xa DOAC, suggesting potential use of this assay for screening or measuring these drugs.

Topics: Administration, Oral; Factor Xa Inhibitors; Humans; Partial Thromboplastin Time; Prothrombin Time; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles

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

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

Observational data and results from post-hoc analyses in clinical trials suggest that direct oral factor Xa inhibitors might increase menstrual bleeding intensity in women of reproductive age, but the extent of this effect is unknown. We aimed to investigate the management and outcomes of vaginal bleeding complications during therapy with direct oral factor Xa inhibitors in a case series of women of reproductive age.. To identify individuals for inclusion in this case series, we searched two sources of prospectively collected data from women of reproductive age treated with direct oral factor Xa inhibitors: the non-interventional Dresden NOAC Registry (NCT01588119), which is based in the administrative district of Dresden (Saxony, Germany), and all locally archived data from phase 3 trials of direct oral factor Xa inhibitors done at University Hospital Carl Gustav Carus Dresden. Vaginal bleeding events were defined as any vaginal bleeding complications as reported by the patient. We collected data on type and dosage of anticoagulation; suspected or confirmed bleeding events, hospital admissions, and mortality; and pattern and management of vaginal bleeding events. For all cases of bleeding identified, we reviewed all available source data to identify examination results suggesting potential underlying anatomical causes of bleeding.. We identified 178 women of reproductive age who received direct oral factor Xa inhibitor therapy, of whom 57 had vaginal bleeding events, including 50 who received rivaroxaban, six who received apixaban, and one who received edoxaban. These 57 women had 72 vaginal bleeding events, including 59 cases of heavy menstrual bleeding and 13 bleeding events unrelated to the menstrual cycle. 51 (86%) of these heavy menstrual bleeding events (two major bleeding events, 17 clinically relevant non-major bleeding events, 32 minor bleeding events) were treated conservatively (eg, change of oral hormone therapy or reduction, temporary interruption, or discontinuation of direct oral factor Xa inhibitor) and the remaining eight (14%) events (three major bleeding events and five clinically relevant non-major bleeding events) required elective surgical or interventional treatment (hysterectomy, curettage, ovary excision, or excision of ovarian cysts). Of the 57 women, 13 (23%) had a second bleeding event and two (4%) had a third event. Nine patients had underlying anatomical abnormalities; compared with patients without abnormalities, these patients had more intense bleeding, more had recurrent bleeding (five [56%] of nine patients with abnormalities vs eight [17%] of 48 patients without abnormalities), and more needed surgical treatment for bleeding (eight [89%] of nine vs zero of 48).. Vaginal bleeding, particularly heavy menstrual bleeding, is a common complication in women of reproductive age on direct oral factor Xa inhibitor therapy. Most cases can be treated conservatively, but patients with severe or recurrent vaginal bleeding complications should be assessed for underlying anatomical abnormalities, which might require surgical or interventional treatment. Further data are needed to provide guidance on prevention and treatment of vaginal bleeding complications in this patient population.. None.

Topics: Administration, Oral; Adult; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Female; Hormone Replacement Therapy; Humans; Menorrhagia; Middle Aged; Progesterone; Prospective Studies; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Uterine Hemorrhage; Venous Thromboembolism

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

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

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

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

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

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

Patients with cancer account for 20 % of cases of venous thromboembolism (VTE). Cancer patients are at increased risk for VTE during the entire course of their disease, also in absence of traditional VTE risk factors. Furthermore, patients with VTE and cancer have an estimated risk of bleeding of 15-20 % per year while on anticoagulant treatment. For these reasons, treatment of acute VTE in patients with cancer remains a clinical challenge. In clinical studies, which included about 27,000 patients, new oral anticoagulants (NOACs) have been shown to be as effective and safe as conventional anticoagulation (heparin given with and followed by vitamin K antagonists) for the treatment of VTE. In these studies, 1227 patients with active cancer were enrolled. Preliminary results of subgroup analyses and meta-analyses of randomized clinical trials suggest that NOACs could represent an alternative to conventional anticoagulation in patients with active cancer. Further "ad hoc" studies evaluating the clinical benefit of treatment with NOACs in patients with VTE and cancer are needed.

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

We compared the cost-utility analysis for edoxaban at both doses with that of dabigatran at both doses, rivaroxaban, and apixaban (non vitamin K antagonist oral anticoagulants, NOAC) in a German population. Data of clinical outcome events were taken from edoxaban's ENGAGE-AF, dabigatran's RE-LY, rivaroxaban's ROCKET, and apixaban's ARISTOTLE trials. The base-case analyses of a 65-year-old person with a CHADS2 score >1 gained 0.17 and 0.21 quality-adjusted life years over warfarin for 30 mg od and 60 mg od edoxaban, respectively. The incremental cost-effectiveness ratio was 50.000 and 68.000 euro per quality-adjusted life years for the higher and lower dose of edoxaban (Monte Carlo simulation). These findings were also similar to those for apixaban and more cost-effective than the other NOAC regimens. The current market costs for direct oral anticoagulants are high in relation to the quality of life gained from a German public health care insurance perspective. The willingness-to-pay threshold was lowest for 60 mg edoxaban compared to all direct oral anticoagulants and for 30 mg edoxaban compared to dabigatran and rivaroxaban.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Cost-Benefit Analysis; Dabigatran; Germany; Humans; Pyrazoles; Pyridines; Pyridones; Quality of Life; Quality-Adjusted Life Years; Rivaroxaban; Thiazoles; Warfarin

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

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

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

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

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

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

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

Venous thromboembolism (VTE) is increasingly diagnosed in pediatric patients, and anticoagulant use in this population has become common, despite the absence of US Food and Drug Administration (FDA) approval for this indication. Guidelines for the use of anticoagulants in pediatrics are largely extrapolated from large randomized controlled trials (RCTs) in adults, smaller dose-finding and observational studies in children, and expert opinion. The recently FDA-approved direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, apixaban, and edoxaban, provide potential advantages over oral vitamin K antagonists and subcutaneous low-molecular-weight heparins (LMWHs). However, key questions arise regarding their potential off-label clinical application in pediatric thromboembolic disease. In this Perspective, we provide background on the use of LMWHs such as enoxaparin as the mainstay of treatment of pediatric provoked VTE; identify key questions and challenges with regard to DOAC trials and future DOAC therapy in pediatric VTE; and discuss applicable lessons learned from the recent pilot/feasibility phase of a large multicenter RCT of anticoagulant duration in pediatric VTE. The challenges and lessons learned present opportunities to improve evidence for anticoagulant therapies in pediatric VTE through future clinical trials.

Topics: Adult; Age Factors; Anticoagulants; Child; Child, Preschool; Clinical Trials as Topic; Dabigatran; Disease Management; Evidence-Based Medicine; Heparin, Low-Molecular-Weight; Humans; Infant; Multicenter Studies as Topic; Practice Guidelines as Topic; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Venous Thromboembolism

Topics: Administration, Oral; Dabigatran; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Substitution; Fibrinolytic Agents; General Practice; Heparin, Low-Molecular-Weight; Humans; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Venous Thrombosis

Topics: Acute Disease; Anticoagulants; Benzimidazoles; Dabigatran; Drug Approval; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Treatment Outcome; Venous Thromboembolism

Although vitamin K antagonists (VKAs) have been the backbone of thromboprophylaxis in nonvalvular atrial fibrillation, their limitations have encouraged the development of a new generation of oral anticoagulants. This review compares the different designs and procedures used to conduct four phase III trials that tested dabigatran, rivaroxaban, apixaban, and edoxaban versus VKAs. Although pharmacologic characteristics and results of the main trials are briefly discussed, this review mainly focuses on study designs, enrollment criteria, populations studied, quality metrics, and transition strategies between oral anticoagulants. While each of the trials was of high quality, performed independently, and led by independent academic groups, substantial differences exist in terms of drug pharmacology and trial characteristics. Caution is advised when comparing results across trials as practicing clinicians strive to personalize anticoagulation treatments for their individual patients. We believe that the differences in the pharmacokinetic and pharmacodynamic profiles of the available novel oral anticoagulants (NOACs), coupled with substantial heterogeneity in the trial populations and designs and procedures used to conduct the trials, support an important role for each of the NOACs dependent upon the specific clinical scenario faced by the practicing clinician.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Clinical Trials, Phase III as Topic; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Research Design; Rivaroxaban; Thiazoles; Thiophenes; Vitamin K; Warfarin

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

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

Direct oral anticoagulants (DOACs) are prescribed for systemic anticoagulation. Fixed doses are recommended, but dose individualization may be warranted. Functional coagulation assays may be available, but their use requires knowledge of the drug taken. To provide alternative methodology for guiding dosage, we have developed and validated a liquid chromatography-mass spectrometric assay for apixaban, dabigatran, edoxaban, and rivaroxaban at the concentrations attained during therapy.. Samples, calibrators, and internal quality controls (100 μL) were mixed with internal standard solution (50 μg/L both dabigatran-13C6 and rivaroxaban-13C6 in acetonitrile) and, after centrifugation (16,400g, 4 minutes), supernatant (100 μL) was injected onto a Cyclone-C18-P-XL TurboFlow column. Analytes were focused onto an Accucore PhenylHexyl (2.1 × 100 mm, 2.6 μm) analytical column and eluted using a methanol + acetonitrile (1 + 1):aqueous ammonium acetate (10 mmol/L) gradient. Data were acquired using high-resolution mass spectrometry in full-scan mode (100-2000 m/z) with data-dependent fragmentation to confirm peak identity. Calibration was linear (1-500 μg/L all analytes).. Total analysis time was 6 minutes. Intra-assay imprecision (% RSD) at 1 μg/L was 2.6%, 4.2%, 17.3%, and 9.5% for apixaban, dabigatran, edoxaban, and rivaroxaban, respectively. Mean recovery was 96%-101%. No signal suppression or enhancement was observed. Apixaban, dabigatran, and rivaroxaban were stable over 3 freeze-thaw cycles, after storage at room temperature, and at 2-8°C for up to 2 weeks. Edoxaban was stable over 3 freeze-thaw cycles but showed a mean deterioration of 16% if stored at 2-8°C (2 weeks) and of 18% and 70% (1 day and 2 weeks, respectively) at room temperature.. The method is suitable for high-throughput therapeutic drug monitoring of DOACs. The acquisition of full scan data allows for the retrospective identification of metabolites. The method can be used to identify a particular DOAC if information on the drug taken is lacking.

Topics: Anticoagulants; Benzimidazoles; beta-Alanine; Chromatography, Liquid; Dabigatran; Humans; Mass Spectrometry; Molecular Structure; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes

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

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

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

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

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

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

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

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

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

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

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

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

Topics: Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Secondary Prevention; Thiazoles; Thiophenes; Venous Thromboembolism

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

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

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

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

Clinical data on the risk factors, incidence, consequences and current treatment options of venous thromboembolism are reviewed. Current guidelines advise anticoagulant treatment for a few weeks or months in immobilized patients treated in hospital, and after major surgery. The initial treatment is based on heparin, followed by vitamin K antagonist treatment. Recently a number of new, partially orally administered medications have undergone clinical investigations and based on the results three of them were also registered for the prevention and treatment of venous thromboembolism. Direct thrombin inhibitors, direct and indirect Factor Xa inhibitors exhibited proven non-inferiority or superiority compared with traditional treatment options. The superior efficacy or non-inferiority was not accompanied with an increase in the bleeding risk. Results of the most important clinical trials are reviewed. Based on these results, prevention and treatment of venous thromboembolism will change substantially in the near future.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Drug Costs; Drugs, Investigational; Factor Xa Inhibitors; Humans; Hungary; Morpholines; Oligosaccharides; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Thrombin; Venous Thromboembolism

Topics: Anticoagulants; Benzimidazoles; Clinical Trials, Phase III as Topic; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes