Target-specific Oral Anticoagulants Research Articles

Comparison of Oral Anticoagulants After Operative Management of Venous Thoracic Outlet Syndrome

The purpose of the study is to review the efficacy of target-specific oral anticoagulants (TSOAC) vs vitamin K antagonist for postsurgical anticoagulation in patients with primary subclavian vein thrombosis. Rivaroxaban and apixaban are newer TSOAC used in deep venous thrombosis (DVT) treatment and prophylaxis. However, the efficacy and safety of TSOAC for the prevention of recurrent deep vein thrombosis after revascularization of upper extremity compression syndromes is largely unknown.

Outcomes of activated prothrombin complex concentrate for direct Xa inhibitor bleeding

Bleeding due to oral anticoagulant therapy is recognized as a high priority drug safety problem [ [1] FDA Adverse Events Reporting System (FAERS)Latest Quarterly Data Files (2017) Food and Drug Administration Web Site. 2021 Google Scholar ]. As the use of direct Xa inhibitors continues to expand, the management of bleeding is an important issue. Andexanet, a modified human factor Xa decoy reversal agent for apixaban or rivaroxaban associated bleeding, is available in some countries however concerns with its use have been expressed [ [2] Peled H. Dau N.Q. Lau H. Key points to consider when evaluating andexxa for formulary addition. Neurocrit. Care. 2020; 33: 20-24 Crossref PubMed Scopus (7) Google Scholar ]. Four factor prothrombin complex concentrate (4FPCC) is an alternative reversal agent which has been used off-label for direct Xa inhibitor bleeding [ 3 Steffel J. et al. The 2018 european heart rhythm association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur. Heart J. 2018; 39: 1330-1393 Crossref PubMed Scopus (1060) Google Scholar , 4 Witt D.M. et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv. 2018; 2: 3257-3291 Crossref PubMed Scopus (188) Google Scholar ]. Four factor PCC is available either as an activated or non-activated product. Limited clinical data exist evaluating activated 4FPCC, FEIBA [anti-inhibitor coagulant complex®, Baxalta US Inc., Lexington MA, USA] as a reversal agent [ 5 Engelbart J.M. et al. Safety and effectiveness of factor eight inhibitor bypassing activity for direct oral anticoagulant-related hemorrhage reversal. Am. J. Emerg. Med. 2019; 37: 214-219 Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar , 6 Mao G. et al. Factor eight inhibitor bypassing agent (FEIBA) for reversal of target-specific oral anticoagulants in life-threatening intracranial bleeding. J. Emerg. Med. 2017; 52: 731-737 Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar ]. As andexanet is not on formulary, the reversal protocol at our institution recommended the use of activated 4FPCC 25–50 IU/kg for direct Xa inhibitor bleeding for situations where reversal is desired. Our goal was to assess the patient characteristics, management and outcomes of activated 4FPCC for reversal of apixaban or rivaroxaban acute bleeding events.

A case study in distributed team science in research using electronic health records.

IntroductionDue to various regulatory barriers, it is increasingly difficult to move pseudonymised routine health data across platforms and among jurisdictions. To tackle this challenge, we summarized five approaches considered to support a scientific research project focused on the risk of the new non-vitamin K Target Specific Oral Anticoagulants (TSOACs) and collaborated between the Farr institute in Wales and Scotland.ApproachIn Wales, routinely collected health records held in the Secure Anonymous Information Linkage (SAIL) Databank were used to identify the study cohort. In Scotland, data was extracted from national dataset resources administered by the eData Research & Innovation Service (eDRIS) and stored in the Scottish National Data Safe Haven. We adopted a federated data and multiple analysts approach, but arranged simultaneous accesses for Welsh and Scottish analysts to generate study cohorts separately by implementing the same algorithm. Our study cohort across two countries was boosted to 6,829 patients towards risk analysis. Source datasets and data types applied to generate cohorts were reviewed and compared by analysts based on both sites to ensure the consistency and harmonised output.DiscussionThis project used a fusion of two approaches among five considered. The approach we adopted is a simple, yet efficient and cost-effective method to ensure consistency in analysis and coherence with multiple governance systems. It has limitations and potentials of extending and scaling. It can also be considered as an initialisation of a developing infrastructure to support a distributed team science approach to research using Electronic Health Records (EHRs) across the UK and more widely.

Distributed team health data science in risk of non-Vitamin K Oral Anticoagulant after Intracranial Haemorrhage

IntroductionNew non-vitamin K Target Specific Oral Anticoagulants (TSOACs) have a favourable risk-benefit profile and debatable cost effectiveness. Large numbers and data from multiple countries in a European study are required to investigate safety issue of TSOACs in subgroups, e.g. people with an intracranial haemorrhage.
 Objectives and ApproachWe developed an approach to rapidly replicate data and analyses to support cross-country distributed research within the UK/EU using Electronic Health Records (EHRs). This project was conceptualised and initialled by linking relevant datasets held in multiple data warehouses, in Scotland with the Scottish National Data Safe Haven, and in Wales through the Secure Anonymised Information Linkage (SAIL) databank. Analysts in Edinburgh and Swansea had remote access to each other’s datasets and worked collaboratively to harmonise variables and analysis scripts. . A common R code script has been produced to harmonise individual data as well as the outputs from the study.
 ResultsThe study screened data on 8M people to develop a cohort that included pseudonymised information of 4,153 individuals in Scotland and 2,676 individuals in Wales, 6,829 individuals in total. Standardised risk analyses were completed in both settings with ongoing work in combining the analyses. In Wales, 39.5% of the patients in the cohort had been admitted to hospitals due to serious vascular events or died caused by these events, after intracranial haemorrhage. Incident rates for male and female are 0.63 and 0.7 respectively. Within the cohort, 0.5% were prescribed with TSOACs and 3% with Warfarin (included as reference). The project is also in the process of including other European jurisdictions.
 Conclusion/ImplicationsThe adopted approach was the simplest, yet most efficient and cost-effective method to ensure consistency in analysis and coherence with currently available governance systems of both safe havens. It can also be considered as an initialisation of developing infrastructure to support research using EHRs across the UK and EU.

Dabigatran (Pradaxa) is safe for extended venous thromboembolism prophylaxis after pancreatic oncologic surgery

Background: Patients undergoing oncologic surgery are at increased risk of venous thromboembolism (VTE). The American College of Chest Physicians and AHPBA recommend low molecular weight heparin for 28 days postoperatively. Injectable anticoagulants are incommodious, and warfarin dosing is inconsistent after gastrointestinal surgery. Oral dabigatran (Pradaxa) is FDA approved for VTE prophylaxis after orthopedic surgery, uses fixed dosing and has an effective reversal agent. Methods: All patients undergoing pancreatic surgery for cancer between Jan and July 2017 were prescribed dabigatran (220 mg daily) from discharge to POD28. Patients were excluded if medically contraindicated. LMWH was prescribed when dabigatran was non-formulary, and other target specific oral anticoagulants were resumed if taken pre-operatively. The primary endpoint was bleeding complications through 90 days. Results: 85 patients were considered for extended VTE prophylaxis. The majority had pancreatic (78%) or ampullary (9%) adenocarcinoma. 74% underwent Whipple, and 21% venous reconstruction. 80 (94%) received extended prophylaxis starting on median POD 7 (IQR: 5,10): 2 refused and contraindications excluded 3 patients. 85% received dabigatran, 11% LMWH, and 4% oral Xa inhibitors. 2 patients (3%) had bleeding complications, both originally having arterial procedures (Clavien IVa & V). An additional 31 HPB oncology patients received dabigatran at provider discretion: 1 suffered a gastrointestinal bleed (Clavien II) on atrial fibrillation dosing. During the period, 2 developed symptomatic VTE prior to discharge on LMWH. Conclusion: Preliminary results show dabigatran to be a safe alternative for extended VTE prophylaxis with regard to bleeding complications. Investigation of relative efficacy is necessary. We cannot currently support dabigatran in patients undergoing arterial reconstruction.

Efficacy of Target Specific Oral Anticoagulants on the Resolution of Left Ventricular Thrombus

Efficacy of Target Specific Oral Anticoagulants on the Resolution of Left Ventricular Thrombus

Laboratory Monitoring or Measurement of Direct Oral Anticoagulants (DOACs): Advantages, Limitations and Future Challenges.

The Direct Oral Anticoagulants (DOACs) represent a new generation of antithrombotic agents, providing direct inhibition of either thrombin (factor IIa; FIIa) or activated factor X (FXa). Around the globe, their use is progressively rising, as these new agents replace the historical anticoagulants (heparin and vitamin K antagonists including warfarin) for various clinical conditions in medical practice. Other acronyms used to designate DOACs include TSOAC (target specific oral anticoagulants) and NOAC (novel; or non-vitamin K antagonist oral anticoagulants). Currently available DOACS include dabigatran (FIIa inhibitor), along with rivaroxaban, apixaban, edoxaban and betrixaban (FXa inhibitors). This narrative review aims to briefly summarise the evidence concerning utility of different laboratory assays for qualitative or quantitative assessment of DOACs, emphasizing the difference between 'drug monitoring' and 'drug measurement' and ultimately discussing advantages and limitations of these processes. Recently, the dogma that these innovative anticoagulant agents will not necessitate laboratory testing has been challenged with the recognition that assessment of drug concentration or activity may be required in some circumstances, although this does not immediately translate to the concept of 'drug monitoring'.

Utilization of Standard and Target-Specific Oral Anticoagulants Among Adults in the United Kingdom With Incident Atrial Fibrillation

New oral anticoagulants (OACs) and updated risk stratification have the potential to improve the quality of care for patients with atrial fibrillation (AF). To describe the time from AF diagnosis to the initiation of an OAC, characteristics associated with treatment, and the incidence of switching OACs, we conducted this retrospective cohort study of 23,018 adults with incident AF receiving care between 2010 and 2014 in 647 primary care practices participating in the United Kingdom Clinical Practice Research Datalink. In patients with moderate to high stroke risk (CHA2DS2-VASc ≥ 2), the median time from diagnosis to OAC initiation decreased from 10 to 2 months. Among 980 at very low stroke risk (CHA2DS2-VASc = 0), 29% received OAC prescriptions after 90 days. Being prescribed an OAC was associated with a history of stroke or transient ischemic attack (relative risk 1.3); severe dementia or psychosis was most associated with not being prescribed an OAC (relative risk 0.3). After 1 year, the risk of OAC switching was higher for patients initiating dabigatran (19%) than warfarin (6%), rivaroxaban (8%), or apixaban (9%). The prescribing of OACs in moderate-to-high-risk patients in the United Kingdom increased annually; 1/3 of very low-risk patients were prescribed OACs contrary to guidance. In conclusion, future research should refine decision-making tools to minimize the unwanted effects of underutilization and overutilization of OACs.

Abstract 519: Inhibition of von Willebrand Factor Activity Does Not Delay Cutaneous Wound Healing

Introduction: Physiologically, von Willebrand Factor (VWF) recruits platelets to sites of injury by binding to exposed collagen and platelet GPIbα, particularly at sites of high shear. VWF is critical to hemostasis, since complete deficiency leads to bleeding as severe as hemophilia. Conversely, VWF plays a key role in arterial thrombosis, as in myocardial infarction and stroke. Despite being an attractive therapeutic target, no agents directed against VWF are currently available. Our group is testing an RNA aptamer that blocks VWF binding to GPIbα as an antithrombotic. We have previously shown that leukocyte influx and cutaneous healing are impaired in a mouse model of hemophilia. We have also found that wound healing is delayed in mice given target specific oral anticoagulants. The purpose of the current study was to determine whether inhibiting VWF would similarly impair wound healing. Methods: We used C57BL/6J mice administered vehicle or VWF aptamer. At the dose selected, aptamer prolonged the saphenous vein bleeding time for the expected 10 day healing period. Healing was assessed in a skin punch biopsy model. Wound size was measured daily, and following sacrifice the wound area harvested for histology. Inflammation (in the absence of tissue injury) was induced by topical application of cantharidin for 24 hours, followed by tissue harvesting. Results: The in vivo efficacy of the aptamer was verified, since bleeding remained prolonged to a level slightly less severe than hemophilia at the end of the experiment (10 days after wounding). There was no difference in time to healing between control and aptamer-treated mice, with all wounds healed at 10 days. There was also no statistically significant difference in wound size at any time. Cantharidin induced a similar level of cellular influx in treated and control mice. Aptamer-treated mice exhibited a slight amount of inflammation-induced hemorrhage, though not the gross hemorrhage observed in thrombocytopenic mice. Conclusion: Inhibition of VWF activity does not delay cutaneous wound closure, despite inducing a severe hemostatic defect. Compared to other antithrombotic strategies, an aptamer against VWF could avert some undesirable side effects on host defense and tissue repair.

Role of agents for reversing the effects of target-specific oral anticoagulants.

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.

Efficacy and safety of the target-specific oral anticoagulants for stroke prevention in atrial fibrillation: the real-life evidence.

The aim of our article is to provide a concise review for clinicians entailing the main studies that evaluated the efficacy and safety of target-specific oral anticoagulants (TSOAs) for thromboembolic stroke prevention in the real-world setting. Atrial fibrillation (AF) is one of the most common supraventricular arrhythmias that requires anticoagulation therapy to prevent stroke and systemic embolism. TSOAs, dabigatran, apixaban and rivaroxaban have become available as an alternative to warfarin anticoagulation in nonvalvular atrial fibrillation (NVAF). Randomized clinical trials showed non-inferior or superior results in efficacy and safety of the TSOAs compared with warfarin for stroke prevention in NVAF patients. For this reason, the 2012 update to the European Society of Cardiology guidelines for the management of AF recommends TSOAs as broadly preferable to vitamin K antagonists (VKAs) in the vast majority of patients with NVAF [Camm et al. 2012]. Although the clinical trial results and the guideline's indications, there is a need for safety and efficacy data from unselected patients in everyday clinical practice. Recently, a large number of studies testing the efficacy and the safety of TSOAs in clinical practice have been published. The aim of our article is to provide a concise review for clinicians, outlining the main studies that evaluated the efficacy and safety of TSOAs for thromboembolic stroke prevention in the real-world setting.

Inpatient Management of Gastrointestinal Bleeding in Patients Receiving Target Specific Oral Anticoagulants

Inpatient Management of Gastrointestinal Bleeding in Patients Receiving Target Specific Oral Anticoagulants

CARDIOEMBOLIC STROKE IN LATVIA: PREVENTION AND LONG-TERM OUTCOME

INTRODUCTION: Untreated non-valvular atrial fibrillation is one of major causes of stroke. The goal of the study was to evaluate the use of antithrombotic medication stroke prevention and assess long-term stroke outcome.METHODS: This study involved 531 cardio embolic stroke patients of the Paul’s Stradins Clinical University Hospital, Riga, Latvia, in 2014. After discharge the patients or their relatives were interviewed by phone after 30, 90, 180, and 365 days. Standardized questions were asked about the patients’ abilities and use of prescribed secondary prevention medication. The results were compared between patient groups, assigned according to prescribed medications.RESULTS: Of all the patients included in the study, 8.9% were using oral anticoagulants before stroke onset. One year after discharge, 1.44% of patients were not using any preventive medication, 23.56% were using antiplatelet agents, 43.27% warfarin, and 31.73% target-specific oral anticoagulants. The one-year mortality rate was 40.7%. The mortality rate was significantly higher in the patient group using no secondary preventive medication or antiplatelet agents compared to the patient group that used oral anticoagulants.CONCLUSION: Cardio embolic stroke primary and secondary prevention in Latvia is lacking. The study outcomes suggest that action is needed to increase the use of oral anticoagulants in primary stroke prevention in patients with atrial fibrillation. Poor function outcomes, dementia, and patients’ incompliance limits the use of oral anticoagulants in secondary prevention.

A summary overview of the new, direct, target-specific oral anticoagulants

In the past 10 years or so, many alternatives to warfarin have been developed the first being the novel oral anticoagulants (NOAC) or better referred to as direct oral anticoagulants (DOAC) or target-specific oral anticoagulants (TSOAC). These drugs have some definite advantages and disadvantages that should be clear to physicians before prescribing any of them for patients. Many clinical trials have provided definitive information about the efficacy and safety of DOACs, yet many physicians remain sceptical about prescribing 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 these drugs affect routine laboratory tests and when monitoring is needed. Knowledge of other drugs that interact with the DOAC and management of severe bleeding will be reviewed and recommendations will be given to all of these concerns.

Risk impact of edoxaban in the management of stroke and venous thromboembolism.

The new generation of target-specific oral anticoagulants is being prescribed for increasing numbers of patients at risk of stroke or venous thromboembolism (VTE). These drugs offer valuable benefits due to fast onset anticoagulation, a fixed anticoagulation effect (allowing administration of specified doses), and no requirement for routine monitoring. Edoxaban is a fast-acting oral anticoagulant, approved for use in the prevention of stroke in patients with nonvalvular atrial fibrillation (AF) and in the treatment of acute VTE. Like many of the new oral anticoagulants, it selectively inhibits factor Xa, in a concentration-dependent manner. Multiple Phase II clinical trials have shown edoxaban to be noninferior to vitamin K antagonists in the prevention of stroke and VTE, with a good safety profile. To date, the pivotal studies to endorse edoxaban’s clinical use have been ENGAGE AF-TIMI and Hokusai-VTE, both of which have compared its efficacy to standard warfarin treatment. This paper aims at reviewing the use of edoxaban in the management of stroke and thromboembolic disease, highlighting the key study results that have led to its current license.

Review of the Target-Specific Oral Anticoagulants in Development for the Treatment and Prevention of Venous Thromboembolism

Anticoagulation therapy is often indicated for the treatment and prevention of venous thromboembolism (VTE). Despite advances in anticoagulant management with parenteral anticoagulants and vitamin K antagonists, limitations to their use still exists, leading to investigation of alternative anticoagulants such as factor Xa inhibitors and direct thrombin inhibitors. To date, 3 target-specific oral anticoagulants (TSOACs) are Food and Drug Administration approved; several other agents are currently in development to optimize VTE management and minimize bleeding risks. The objective of this systematic review article is to provide clinicians an overview of the clinical evidence on the investigational TSOACs for the treatment and prevention of VTE. Of the agents in development, edoxaban holds the most promise due to robust data supporting its clinical benefit with a similar bleeding risk to currently approved agents. Clinicians should understand the TSOACs under investigation, since differences in pharmacokinetics and pharmacodynamics may influence clinical decision making and agent selection for management of VTE. Currently, no direct comparisons between TSOACs have been conducted. Agents under investigation have yet to overcome the major limitations of the currently existing TSOACs. Further studies are necessary to clarify which TSOAC agent is best for management of VTE in clinical practice.

Managing Extended Oral Anticoagulation After Unprovoked Venous Thromboembolism.

Venous thromboembolism (VTE), which includes deep venous thrombosis and pulmonary embolism, is a major public health problem associated with increased morbidity and mortality. Despite the high recurrence risk associated with unprovoked VTE, extended anticoagulation remains controversial. Oral antithrombotic agents for extended VTE treatment comprise the vitamin K antagonists, aspirin, and the direct oral anticoagulants (also known as target-specific oral anticoagulants and formerly known as the new or novel oral anticoagulants) including rivaroxaban, dabigatran, apixaban, and edoxaban. The efficacy of these anticoagulants in reducing the risk of VTE recurrence (>80%-90% relative risk reduction) is offset by the risk of major bleeding that approaches 3% per year. Stratifying risks of recurrence and bleeding to identify patients at low, intermediate, or high risk and carefully considering the pharmacologic profile of the antithrombotic agents will help clinicians in choosing the optimal anticoagulant and duration and/or surveillance strategy. This review will discuss the current guidelines for extended VTE treatment, review the clinical trials involving the direct oral anticoagulants, and present the clinical considerations and concerns involving extended therapy.

Which antidotes are available for the novel oral anticoagulants?

Use of novel (or target-specific) oral anticoagulants continues to increase. This article reviews idarucizumab and andexanet alfa, two antidotes that can be used to reverse anticoagulation in patients needing emergency surgery or with life-threatening bleeding.

Pharmacologic Therapies in Anticoagulation.

Anticoagulants are beneficial for prevention and treatment of venous thromboembolism and stroke prevention in atrial fibrillation. The development of target-specific oral anticoagulants is changing the landscape of anticoagulation therapy and created growing interest on this subject. Understanding the pharmacology of different anticoagulants is the first step to adequately treat patients with best available therapy while avoiding serious bleeding complications. This article reviews the pharmacology of the main anticoagulant classes (vitamin K antagonists, direct oral anticoagulants, and heparins) and their clinical indications based on evidence-based data currently available in the literature.

MECHANICAL AORTIC VALVE THROMBOSIS ON RIVAROXABAN

Target specific oral anticoagulants (TSOACs) are approved for stroke prevention in nonvalvular atrial fibrillation and for prevention and treatment of deep vein thrombosis and pulmonary embolism. Currently they are contraindicated in patients with mechanical valves. In the absence of appropriate