Target-specific Oral Anticoagulants Research Articles

Stroke prevention in nonvalvular atrial fibrillation: update on target-specific oral anticoagulants.

Atrial fibrillation is the most common arrhythmia in adults, and the risk for stroke is increased five-fold. Efforts should be made to educate health care providers to understand the importance of using risk stratification tools. New oral anticoagulants are available for thromboembolic stroke prevention, and knowledge of their clinical indications and use is essential.

Use Patterns and Unlabeled Uses of Target-Specific Oral Anticoagulants: A Single-Center Experience.

Background: Target-specific oral anticoagulants (TSOAs) have advantages and disadvantages over warfarin, and they differ by indication, dosage adjustment, and drug interactions. Objective: The purpose of this retrospective cohort study is to determine use patterns and unlabeled uses of TSOAs. Methods: From July 1, 2012, to April 30, 2014, orders for warfarin, dabigatran, rivaroxaban, or apixaban in a tertiary medical center were included. Electronic medical records were reviewed to collect information regarding characteristics of the patients receiving these medications. Unlabeled use was defined as an indication or dose not approved by the US Food and Drug Administration. The percentage of orders for each study drug per month and the percentage of orders for each TSOA that contained an unlabeled use were calculated. Results: Of a total of 869 orders, 140 (16.1%) were for TSOAs (13 dabigatran, 97 rivaroxaban, and 30 apixaban orders). Compared with the first 4 months of the study period, the monthly percentage of orders for a TSOA increased by 2.5-fold in the last 4 months. Of the 3 TSOAs, only orders for dabigatran decreased (5.6% in July 2012 vs 0% in April 2014). Of the 140 TSOA orders, 28 (20.0 %) were unlabeled uses (3 unlabeled indications and 25 unlabeled dose), which included 16 unlabeled renally adjusted doses. The percentage of unlabeled uses did not significantly differ by TSOA. Conclusion: The use of TSOAs has increased and unlabeled uses are common. These data provide opportunities for quality improvement in the use of TSOA in clinical practice.

Effect of rivaroxaban versus warfarin on health care costs among nonvalvular atrial fibrillation patients: observations from rivaroxaban users and matched warfarin users.

IntroductionNew target-specific oral anticoagulants may have benefits, such as shorter hospital length of stay, compared to warfarin in patients with nonvalvular atrial fibrillation (NVAF). This study aimed to assess, among patients with NVAF, the effect of rivaroxaban versus warfarin on health care costs in a cohort of rivaroxaban users and matched warfarin users.MethodsHealth care claims from the Humana database from 5/2011 to 12/2012 were analyzed. Adult patients newly initiated on rivaroxaban or warfarin with ≥2 atrial fibrillation (AF) diagnoses (The International Classification of Diseases, Ninth Revision, Clinical Modification: 427.31) and without valvular AF were identified. Based on propensity score methods, warfarin patients were matched 1:1 to rivaroxaban patients. Patients were observed up to end of data, end of insurance coverage, death, a switch to another anticoagulant, or treatment nonpersistence. Health care costs [hospitalization, emergency room (ER), outpatient, and pharmacy costs] were evaluated using Lin’s method.ResultsMatches were found for all rivaroxaban patients, and characteristics of the matched groups (n = 2253 per group) were well balanced. Estimated mean all-cause and AF-related hospitalization costs were significantly lower for rivaroxaban versus warfarin patients (all-cause: $5411 vs. $7427, P = 0.047; AF-related: $2872 vs. $4147, P = 0.020). Corresponding estimated mean all-cause outpatient visit costs were also significantly lower, but estimated mean pharmacy costs were significantly higher for rivaroxaban patients ($5316 vs. $2620, P < 0.001). Although estimated mean costs of ER visits were higher for rivaroxaban users compared to those of warfarin users, differences were not statistically significant. Including anticoagulant costs, mean overall total all-cause costs were comparable for rivaroxaban versus warfarin users due to cost offset from a reduction in the number and length of hospitalizations and number of outpatient visits ($17,590 vs. $18,676, P = 0.542).ConclusionDespite higher anticoagulant cost, mean overall total all-cause and AF-related cost remains comparable for patients with NVAF treated with rivaroxaban versus warfarin due to the cost offset from reduced health care resource utilization.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-015-0189-1) contains supplementary material, which is available to authorized users.

A guide to the use of anticoagulant drugs in children.

Increasing thrombotic complications in children with complex medication conditions have led to more widespread use of anticoagulants [Raffini et al. in Pediatrics 124(4):1001-8, 2009]. While current guidelines for the management of antithrombotic therapy in neonates and children exist, they are based on low- and very low-quality evidence [Monagle et al. in Chest 141(2 Suppl):e737-801S, 2012]. Despite numerous differences, current anticoagulation practice is largely extrapolated from adult studies. This is sub-optimal, particularly in neonates who have a rapidly evolving hemostatic system. The majority of pediatric patients have underlying medical conditions that may significantly influence drug choice and bleeding risk. This article reviews the use of anticoagulants in children with thrombosis, focusing on practical aspects such as dosing, monitoring, and complications. Low molecular weight heparin has become the preferred anticoagulant in children, although unfractionated heparin and warfarin remain frequently used. Other anticoagulants, including fondaparinux, direct thrombin inhibitors, and the newer target-specific oral anticoagulants are also discussed. Given the many unique challenges surrounding the use of anticoagulants in children, pediatric hospitals should have written practice guidelines as well as experienced providers to care for children with thrombosis. This is an evolving field, and further studies of the use of anticoagulants in neonates and children are greatly needed to help optimize care.

Laboratory testing in the era of direct or non-vitamin K antagonist oral anticoagulants: a practical guide to measuring their activity and avoiding diagnostic errors.

A new generation of antithrombotic agents has recently emerged. These provide direct inhibition of either thrombin (factor IIa [FIIa]) or FXa, and are increasingly replacing the classical anticoagulants (heparin and coumarins such as warfarin) in clinical practice for a variety of conditions. These agents have been designated several acronyms, including NOACs, DOACs, and TSOACs, respectively, referring to new (novel; non-vitamin K antagonist) oral anticoagulants, direct oral anticoagulants, and target-specific oral anticoagulants, and currently include dabigatran (FIIa inhibitor), and rivaroxaban, apixaban, edoxaban, and betrixaban (FXa inhibitors). The pervading mantra that NOACs do not require laboratory monitoring is countered by ongoing recognition that laboratory testing for drug effects is needed in many situations. Moreover, since these agents "do not require" laboratory monitoring, some clinicians inappropriately take this to mean that they do not affect hemostasis tests. This review aims to briefly review the laboratory studies that have evaluated the NOACs against a wide range of laboratory assays to assess utility for qualitative or quantitative measurements of these drugs, as well as interferences that may cause misdiagnosis of hemostatic defects. Point of care testing, including use of alternate samples such as urine and serum, is also under development but is not covered extensively in this review. The main aims of this article are to provide practical guidance to general laboratory testing for NOACs, as well as to help avoid diagnostic errors associated with hemostasis testing performed on samples from treated patients, as these currently comprise major challenges to hemostasis laboratories in the era of the NOACs.

Recent Advances in the Development of Specific Antidotes for Target-Specific Oral Anticoagulants

Warfarin, a vitamin K antagonist, has been the only orally available anticoagulant for>60years. During the past decade, the U.S. Food and Drug Administration has approved several target-specific oral anticoagulants (TSOACs) for the prophylaxis and treatment of arterial and venous thromboembolism and stroke prevention in patients with nonvalvular atrial fibrillation. These new agents have several advantages over warfarin including more predictable pharmacokinetics and pharmacodynamics, fewer food and drug interactions, and lack of need for routine coagulation monitoring. However, unlike warfarin, currently no antidotes are available to reverse the anticoagulant effect of TSOACs. Specific antidotes for TSOACs may not be needed in most situations due to their short half-life, yet the absence of antidotes for these agents is a concern, especially in emergent situations such as life-threatening major bleeding or nonelective major surgery. Several specific antidotes for TSOACs including idarucizumab, andexanet alfa, and aripazine have been developed and have shown promise in early clinical trials evaluating their efficacy and safety. In this narrative review, the progress made in developing specific antidotes for TSOACs is summarized based on the latest available preclinical and clinical data.

New developments in pediatric venous thromboembolism and anticoagulation, including the target-specific oral anticoagulants.

Pediatric venous thromboembolism (VTE) can affect children of all ages, requiring considerable pharmacologic intervention and is often associated with significant morbidity. Current research efforts are directed toward the development of risk-stratified VTE prevention strategies employing pharmacologic thromboprophylaxis, the optimization of conventional anticoagulation, and the investigation of the safety and efficacy of target-specific oral anticoagulants (TSOACs) in children. Recent research has considerably improved the understanding of risk factors of hospital-acquired VTE and how these factors may be employed in risk-stratified paradigms for VTE prevention in children. Additional insight has been gained in the optimization of conventional anticoagulants in special populations such as neonates and children with inflammatory conditions, and in improving the overall safety and compliance with periprocedural anticoagulation and the use of home International Normalized Ratio monitoring. Furthermore, the use of TSOACs has been described in children and is the focus of numerous ongoing clinical trials that are evaluating the safety and efficacy of these agents in children with VTE. Identification of hospital-acquired VTE risk factors may inform pediatric VTE prevention strategies. Although initial use of TSOACs may be promising, investigation of safety and efficacy in children is still underway.

Managing target-specific oral anticoagulant associated bleeding including an update on pharmacological reversal agents.

Target-specific oral anticoagulants (TSOACs) dabigatran, rivaroxaban and apixaban are approved for the prevention and treatment of thromboembolism in several clinical settings. Bleeding is the major complication of anticoagulant therapy, including TSOACs, and anticoagulant reversal strategies are highly desired for the management of anticoagulant-associated major bleeding in addition to maximum supportive care and procedural/surgical intervention. Unlike VKAs for which vitamin K and coagulation factor replacement with prothrombin complex concentrate (PCC) can restore hemostasis, there are no clinically available agents proven to reverse TSOAC anticoagulant effect and ameliorate TSOAC-related major bleeding. This narrative review critically evaluates the evidence for TSOAC reversal using non-specific reversal agents PCC, activated PCC (APCC) and recombinant activated factor VII (rVIIa) which have been assessed primarily using in vitro experiments, animal models and healthy human volunteers. Aripazine is a novel agent undergoing clinical development for non-specific anticoagulant reversal, including TSOACs. Data are presented regarding specific reversal agents idarucizumab (dabigatran) and andexanet alfa (oral factor Xa inhibitors) currently being evaluated in clinical trials. A practical approach to management of patients with TSOAC-associated bleeding is also provided. There is an urgent need for clinical studies that evaluate the efficacy and safety of reversal strategies for TSOAC-related major bleeding with assessment of clinical outcomes such as bleeding and mortality.

Changing practice of anticoagulation: will target-specific anticoagulants replace 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.

The new, direct, target-specific oral anticoagulants

In recent years, numerous alternatives to VKAs have been developed, the first competitors to warfarin are the novel oral anticoagulants (NOAC) or better referred to as Direct Oral Anti-Coagulant (DOAC) or Target Specific Oral Anti-coagulant (TSOAC): These drugs have definite advantages and disadvantages that should be clear to the physicians before prescribing any of them for patients. Many clinical trials, which involved thousands of patients provided definite information about the efficacy and the safety of DOACs, yet, many physicians remain reluctant to prescribe these drugs due to lack of answers to real world questions. The concerns are directed towards appropriate patient selection (The choice should be made according to age, renal function, compliance, cost, clinical condition, intake of other drugs), the mechanism of switching between agents. How to manage regarding any procedural measurement? How these drugs affect routine laboratory tests and when do we need monitoring? Knowledge of other drugs that interact with the DOAC and management of severe bleeding will be reviewed and recommendations will be given to all these concerns.

A Comparative Evaluation of Adverse Drug Events and Incidence of Stroke amongst the Target Specific Oral Anticoagulants

A Comparative Evaluation of Adverse Drug Events and Incidence of Stroke amongst the Target Specific Oral Anticoagulants

Reversal of anticoagulant effects in patients with intracerebral hemorrhage.

Anticoagulant therapies are increasingly being used for the treatment and prevention of thromboembolic diseases. A growing incidence of anticoagulant-associated intracranial hemorrhage (AICH) has accompanied the rise in their use. Although the rate of intracerebral hemorrhage (ICH) in patients receiving anticoagulation therapies such as heparin and target-specific oral anticoagulants (TSOAs) is significantly lower than that of vitamin K antagonists (VKAs), the mortality rate remains high. TSOAs have only recently become available for use in clinical practice, and presently, there is a paucity of both clinical data and evidence-based guidelines to assist in the management of TSOA-associated intracerebral hemorrhage. In this article, we review current literature and provide physicians with diagnostic and therapeutic considerations for the management of AICH.

Bleeding complications of targeted oral anticoagulants: what is the risk?

The vitamin K antagonists (VKAs) are a widely used class of agent to prevent thromboembolism. In recent years, numerous alternatives to VKAs have been developed, the target-specific oral anticoagulants (TSOACs), which are available in clinical practice. Currently available agents target thrombin and factor Xa. The most significant side effect of these agents, as with VKAs, is the development of bleeding complications. In this review, the risks of major bleeding complications with the TSOACs will be discussed. Data from meta-analyses, randomized controlled trials, and observational studies will be used to highlight bleeding complications associated with TSOACs and warfarin. We highlight the most common causes of major bleeding, GI and intracranial hemorrhage.

The target-specific oral anticoagulants: practical considerations

More than 4 years have passed since the first approval of a target-specific oral anticoagulant (TSOAC) in the United States, and the number of clinicians who have prescribed (or considered prescribing) one or more of these medications is increasing. Although these agents may, in properly selected patients, offer advantages over more traditional therapies, their lack of familiarity can be intimidating. Clinicians who are prescribing the TSOACs face a number of management questions not definitively answered by the registration trials. This chapter reviews some of these situations, including updated information on the periprocedural management of TSOACs and the latest evidence about how to best measure TSOAC effect. The lack of an antidote and other considerations that may be relevant when deciding between newer and more traditional anticoagulant medications are also discussed.

Prothrombin Complex Concentrate (4PCC): A Review of its Use in Reversal of Vitamin K Antagonists

Bleeding continues to be a major adverse drug event associated with warfarin anticoagulation. The cornerstone of warfarin-related bleeding management involves repletion of affected plasma coagulation factor levels. Prothrombin complex concentrate (human) is a 4-factor prothrombin complex concentrate that contains vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulant proteins C and S. It recently received Food and Drug Administration approval for warfarin reversal for patients with major bleeding or requiring urgent surgery or other invasive procedures. Its role in reversing target-specific oral anticoagulants appears to be limited to the Factor Xa inhibitors as an emergent intervention.

The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis

AbstractVitamin K antagonists (VKAs) have been the standard of care for treatment of thromboembolic diseases. Target-specific oral anticoagulants (TSOACs) have been developed and found to be at least noninferior to VKAs with regard to efficacy, but the risk of bleeding with TSOACs remains controversial. We performed a systematic review and meta-analysis of phase-3 randomized controlled trials (RCTs) to assess the bleeding side effects of TSOACs compared with VKAs in patients with venous thromboembolism or atrial fibrillation. We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials; conference abstracts; and www.clinicaltrials.gov with no language restriction. Two reviewers independently performed study selection, data extraction, and study quality assessment. Twelve RCTs involving 102 607 patients were retrieved. TSOACs significantly reduced the risk of overall major bleeding (relative risk [RR] 0.72, P < .01), fatal bleeding (RR 0.53, P < .01), intracranial bleeding (RR 0.43, P < .01), clinically relevant nonmajor bleeding (RR 0.78, P < .01), and total bleeding (RR 0.76, P < .01). There was no significant difference in major gastrointestinal bleeding between TSOACs and VKAs (RR 0.94, P = .62). When compared with VKAs, TSOACs are associated with less major bleeding, fatal bleeding, intracranial bleeding, clinically relevant nonmajor bleeding, and total bleeding. Additionally, TSOACs do not increase the risk of gastrointestinal bleeding.

When patients on target-specific oral anticoagulants need surgery.

The target-specific oral anticoagulants (TSOACs), eg, dabigatran, rivaroxaban, and apixaban, are changing the way we manage thromboembolic disease. At the same time, many clinicians wonder how best to manage TSOAC therapy when patients need surgery. An in-depth understanding of these drugs is essential to minimize the risk of bleeding and thrombosis perioperatively.

Managing Bleeding and Emergency Reversal of Newer Oral Anticoagulants: A Review for Primary Care Providers

The therapeutic landscape for anticoagulation management is undergoing a shift from the use of traditional anticlotting agents such as heparins and warfarin as the only options to the growing adoption of newer target-specific oral anticoagulants (TSOACs) with novel mechanisms of action. Dabigatran, the first TSOAC approved for use in the United States, is a direct competitive inhibitor of thrombin. It has predictable kinetics, with an elimination half-life of 12 to 17 hours in healthy volunteers. Apixaban and rivaroxaban are selective inhibitors of factor Xa, and also display first-order kinetics. In younger healthy individuals, apixaban has an apparent half-life of approximately 12 hours, whereas rivaroxaban has an elimination half-life of 5 to 9 hours. Understanding the pharmacologic properties of these newer drugs can lead to better insights regarding their respective safety and efficacy profiles and their application in clinical practice. Laboratory assessments have been developed to measure the anticoagulant efficacy of these newer agents. However, the results of these tests can be highly variable, and are therefore not always useful for monitoring the anticoagulation effects of these agents. In addition, several strategies have been documented for the potential reversal of the anticoagulant effects of these drugs, from the temporary discontinuation of an agent before elective surgery to suggested emergency procedures in the case of major bleeding events. New, specific reversal agents for dabigatran, apixaban, and rivaroxaban are currently being developed, and dabigatran has received fast-track designation from the US Food and Drug Administration. Until comprehensive clinical guidelines are developed, institutions involved in emergency care should establish their own procedures for the management of patients undergoing anticoagulation who require emergency treatment. These protocols should include appropriate laboratory testing to assess anticoagulant activity as part of the inpatient workup if time allows, and the potential use of hemodialysis, prohemostatic agents, and reversal agents when available.

Reversal of the Target Specific Oral Anticoagulants: A Practical Approach to a Situation With Incomplete Information

Reversal of the Target Specific Oral Anticoagulants: A Practical Approach to a Situation With Incomplete Information

Clinical use of rivaroxaban: pharmacokinetic and pharmacodynamic rationale for dosing regimens in different indications.

Target-specific oral anticoagulants have become increasingly available as alternatives to traditional agents for the management of a number of thromboembolic disorders. To date, the direct Factor Xa inhibitor rivaroxaban is the most widely approved of the new agents. The dosing of rivaroxaban varies and adheres to specific schedules in each of the clinical settings in which it has been investigated. These regimens were devised based on the results of phase II dose-finding studies and/or pharmacokinetic modeling, and were demonstrated to be successful in randomized, phase III studies. In most cases, the pharmacodynamic profile of rivaroxaban permits once-daily dosing. A once-daily dose is indicated for the prevention of venous thromboembolism (VTE) in patients undergoing hip or knee replacement surgery, the long-term prevention of stroke in patients with non-valvular atrial fibrillation, and the long-term secondary prevention of recurrent VTE. Twice-daily dosing is required in the acute phase of treatment in patients with VTE and in the combination of rivaroxaban with standard single or dual antiplatelet therapy for secondary prevention after acute coronary syndrome events. This article reviews the empirical and clinical rationale supporting the dose regimens of rivaroxaban in each clinical setting.