The long path to NOAC

Phlebologie ◽  
2016 ◽  
Vol 45 (04) ◽  
pp. 245-251
Author(s):  
S. Haas
Keyword(s):  
Mode Of Action ◽  
Vitamin K Antagonists ◽  
Factor Xa ◽  
Thrombin Inhibitor ◽  
Renal Elimination ◽  
Early 21St Century ◽  
Recombinant Production ◽  
Anticoagulant Drugs ◽  
Venous Thromboembolic ◽  
Dosing Regimens

SummaryThe discovery of anticoagulant drugs occurred at a time when the process of blood coagulation only had been roughly described and their mode of action was unknown. Nevertheless, heparin – which was discovered 100 years ago – and warfarin – which was developed in the 1920s – had taken off on a triumphal course which is unique in medical history. The synthesis of anticoagulants with targeted mode of action was only achieved at the end of the last century, e. g. the inhibitor of factor Xa fondaparinux or the recombinant production of the direct thrombin inhibitor hirudin, closely followed by the synthesis of the direct oral inhibitors of factor Xa and thrombin. These compounds had been clinically developed in the early 21st century and meanwhile, they have become available for several indications. Dabigatran is the only thrombin inhibitor and rivaroxaban, apixaban and edoxaban are the three factor Xa inhibitors which entered the market and have started replacing the conventional anticoagulants for treatment of venous thromboembolic complications and for prevention of stroke in patients with atrial fibrillation. They have several characteristics in common such as a reproducible bioavailability, much shorter halflives than vitamin K antagonists, low interaction with other drugs, fixed dosing regimens without the necessity for routine coagulation controls and a better risk-/benefit profile than conventional anticoagulants. However, there are differences between the various compounds with regard to metabolism, renal elimination and the various dosing regimens which definitely need to be considered when prescribed to various patient populations.

scholarly journals The Severity of Intracranial Hemorrhages Measured by Free Hemoglobin in the Brain Depends on the Anticoagulant Class: Experimental Data

2017 ◽  
Vol 2017 ◽  
pp. 1-4 ◽  
Author(s):  
Kyle M. Ware ◽  
Douglas L. Feinstein ◽  
Israel Rubinstein ◽  
Prudhvi Battula ◽  
Jose Otero ◽  
...  
Keyword(s):  
Vitamin K ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Hemoglobin Concentration ◽  
Thrombin Inhibitor ◽  
Free Hemoglobin ◽  
Intracranial Hemorrhages ◽  
The Brain

Background and Purpose. Anticoagulant therapy is broadly used to prevent thromboembolic events. Intracranial hemorrhages are serious complications of anticoagulation, especially with warfarin. Direct oral anticoagulants reduce but do not eliminate the risk of intracranial hemorrhages. The aim of this study is to determine the degree of intracranial hemorrhage after application of anticoagulants without additional triggers. Methods. Rats were treated with different anticoagulant classes (vitamin K antagonists, heparin, direct thrombin inhibitor, and factor Xa inhibitor). Brain hemorrhages were assessed by the free hemoglobin concentration in the brain parenchyma. Results. Vitamin K antagonists (warfarin and brodifacoum) significantly increased free hemoglobin in the brain. Among direct oral anticoagulants, thrombin inhibitor dabigatran also significantly increased free hemoglobin in the brain, whereas treatment with factor Xa inhibitor rivaroxaban did not have significant effect on the free hemoglobin concentration. Conclusions. Our data indicates that the severity of brain hemorrhages depends on the anticoagulant class and it is more pronounced with vitamin K antagonists.

scholarly journals Update on Edoxaban for the Prevention and Treatment of Thromboembolism: Clinical Applications Based on Current Evidence

2015 ◽  
Vol 2015 ◽  
pp. 1-19 ◽  
Author(s):  
Ali Zalpour ◽  
Thein Hlaing Oo
Keyword(s):  
Vitamin K Antagonists ◽  
Dabigatran Etexilate ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Coagulation Factors ◽  
Current Evidence ◽  
Thrombin Inhibitor ◽  
Prevention And Treatment ◽  
Financial Impacts

Vitamin K antagonists (VKA) and heparins have been utilized for the prevention and treatment of thromboembolism (arterial and venous) for decades. Targeting and inhibiting specific coagulation factors have led to new discoveries in the pharmacotherapy of thromboembolism management. These targeted anticoagulants are known as direct oral anticoagulants (DOACs). Two pharmacologically distinct classes of targeted agents are dabigatran etexilate (Direct Thrombin Inhibitor (DTI)) and rivaroxaban, apixaban, and edoxaban (direct oral factor Xa inhibitors (OFXaIs)). Emerging evidence from the clinical trials has shown that DOACs are noninferior to VKA or low-molecular-weight heparins in the prevention and treatment of thromboembolism. This review examines the role of edoxaban, a recently approved OFXaI, in the prevention and treatment of thromboembolism based on the available published literature. The management of edoxaban in the perioperative setting, reversibility in bleeding cases, its role in cancer patients, the relevance of drug-drug interactions, patient satisfaction, financial impacts, and patient education will be discussed.

How Do We Treat Pregnancy-Related Venous Thromboembolism?

2019 ◽  
Vol 40 (01) ◽  
pp. 054-063 ◽  
Author(s):  
Birgit Linnemann ◽  
Birgit Seelbach-Goebel ◽  
Susanne Heimerl ◽  
Christina Hart
Keyword(s):  
Venous Thromboembolism ◽  
Vitamin K Antagonists ◽  
Treatment Strategies ◽  
Factor Xa ◽  
Study Data ◽  
Time Interval ◽  
Uncomplicated Pregnancy ◽  
Delivery Date ◽  
Maternal Morbidity And Mortality ◽  
Dosing Regimens

AbstractVenous thromboembolism (VTE) is a major cause of maternal morbidity and mortality during pregnancy and the postpartum period. Due to a lack of adequate study data, therapeutic strategies for pregnancy-related VTE are deduced from observational studies and extrapolated from recommendations for nonpregnant patients. Because heparins do not cross the placenta, weight-adjusted therapeutic-dose low-molecular-weight heparins (LMWHs) are the anticoagulant treatment of choice in cases of VTE during pregnancy. Once- and twice-daily dosing regimens are suitable. There is no evidence that measurement of factor Xa activities and consecutive LMWH dose adjustments improve clinical outcomes. There is no support for the routine use of vitamin K antagonists, direct oral thrombin or factor Xa inhibitors, fondaparinux, or danaparoid in uncomplicated pregnancy-related VTE. Management of delivery deserves special attention, and treatment strategies depend on the time interval between the diagnosis of acute VTE and the expected delivery date. In lactating women, an overlapping switch from LMWH to warfarin is possible. Anticoagulation should be continued for at least 6 weeks postpartum or for a minimum period of 3 months.

Novel oral anticoagulants - key messages for the angiologist

VASA ◽  
2012 ◽  
Vol 41 (3) ◽  
pp. 177-191 ◽  
Author(s):  
Haas ◽  
Spannagl ◽  
M. Schellong
Keyword(s):  
Clinical Evidence ◽  
Vitamin K Antagonists ◽  
Dabigatran Etexilate ◽  
Oral Anticoagulants ◽  
Factor Xa ◽  
Novel Oral Anticoagulants ◽  
Bleeding Complications ◽  
Thrombin Inhibitor ◽  
Clinical Scenarios ◽  
Major Orthopaedic Surgery

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

Direct inhibitors of coagulation proteins – the end of the heparin and low-molecular-weight heparin era for anticoagulant therapy?

2009 ◽  
Vol 102 (11) ◽  
pp. 892-899 ◽  
Author(s):  
Elisabeth Perzborn ◽  
Stefan Heitmeier ◽  
Georges von Degenfeld ◽  
Elke Dittrich-Wengenroth ◽  
Anja Buchmüller ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Vitamin K Antagonists ◽  
Factor Xa ◽  
Coagulation Cascade ◽  
Thrombin Inhibitor ◽  
Low Molecular Weight ◽  
Direct Factor ◽  
New Anticoagulants ◽  
Coagulation Proteins ◽  
The Eu

SummaryHeparins, either unfractionated or low-molecular-weight (UFH and LMWHs), and vitamin K antagonists (VKAs) are currently the anticoagulants of choice for the prevention of post-operative venous thromboembolism (VTE) and for the treatment of acute venous and arterial thromboembolism. While VKAs are widely used in the US, LMWHs are the standard of care in the EU. Although efficacious, these agents are associated with a number of drawbacks, such as the risk of heparin-induced thrombocytopenia, the need for frequent coagulation monitoring in the case of UFH and VKAs, and the parenteral mode of administration in the case of heparins, which can lead to problems associated with patient compliance. There is a need for new anticoagulants that overcome these limitations. Direct, small-molecule inhibitors of coagulation proteins targeting a single enzyme in the coagulation cascade – particularly thrombin or Factor Xa – have been developed in recent years. Two agents, the direct thrombin inhibitor dabigatran and the direct Factor Xa inhibitor rivaroxaban, have recently been approved in the EU and several other countries for the prevention of VTE after total hip or knee replacement surgery. Here we will review data that suggest that the antithrombin-independent mechanism of action of these agents, particularly that of direct Factor Xa inhibitors, leads to increased efficacy with similar safety profiles compared with the antithrombin-dependent heparins. Although the end of the heparins era is not to be expected, the new anticoagulants presented in this review potentially represent the future of anticoagulation.

scholarly journals Using direct oral anticoagulants (DOACs) in cancer and other high-risk populations

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 125-131 ◽  
Author(s):  
Nick van Es ◽  
Harry R. Büller
Keyword(s):  
High Risk ◽  
Vitamin K ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Thrombin Inhibitor ◽  
Efficacy And Safety ◽  
Practical Advantage ◽  
High Risk Populations

Abstract The major practical advantage of the direct oral anticoagulants (DOACs), comprising the thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban, edoxaban, and rivaroxaban, over vitamin K antagonists is their fixed dosing without the need for laboratory monitoring. With the recent, rapid introduction of the DOACs for the treatment of acute venous thromboembolism (VTE), clinicians are now faced with various questions regarding the efficacy and safety of these compounds overall and in specific high-risk populations. The collective evidence from 6 large clinical trials involving 27,000 patients has demonstrated that DOACs are as effective as vitamin K antagonists (VKA) in preventing recurrent VTE while being associated with a significantly lower risk of major bleeding. These findings are consistent in subgroups of patients with pulmonary embolism, the elderly, and those patients with a high body weight or moderate renal insufficiency, making these agents suitable for a broad spectrum of patients with VTE. DOACs are also an attractive treatment option in patients with VTE and concomitant cancer, thrombotic antiphospholipid syndrome, or heparin-induced thrombocytopenia, but the currently available clinical data is insufficient to make evidence-based recommendations on the use of DOACs in these settings. Several studies evaluating the efficacy and safety of DOACs in these high-risk populations are underway.

New oral anticoagulant drugs in cardiovascular disease

2010 ◽  
Vol 104 (07) ◽  
pp. 49-60 ◽  
Author(s):  
Gregory Lip ◽  
Karlheinz Peter ◽  
Ingo Ahrens
Keyword(s):  
Cardiovascular Disease ◽  
Oral Anticoagulation ◽  
Clinical Investigation ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Factor Xa ◽  
Novel Oral Anticoagulants ◽  
Response To Treatment ◽  
Coagulation System ◽  
Thrombin Inhibitor

SummaryOral anticoagulation has been limited to vitamin K antagonists (VKAs) for over 60 years. VKAs are effective and recommended for the prevention of venous and arterial thromboembolism in cardiovascular disease, but their pharmacodynamics are difficult to predict and the highly variable interindividual and intraindividual response to treatment accounts for the need of continuous monitoring. This prompted the intensive exploration of numerous substances within the last decade in an attempt to meet the shortcomings of current oral anticoagulation with VKAs. The development and clinical investigation of two novel groups of oral anticoagulants targeting central factors of the coagulation system either factor Xa or thrombin (factor IIa) has now reached the daily clinical practice with the approval of the oral direct thrombin inhibitor dabigatran etexilate and the oral direct factor Xa inhibitor rivaroxaban. Ongoing clinical trials are investigating these substances and other novel oral anticoagulants with similar mechanisms of action in patients with atrial fibrillation and acute coronary syndromes. This review article discusses the clinical evaluation and pharmacological properties of novel oral anticoagulants in late and earlier stages of clinical development, thereby providing a critical analysis and an outlook on the future of oral anticoagulation in cardiovascular disease.

Novel Oral Anticoagulants: Efficacy, Laboratory Measurement, and Approaches to Emergent Reversal

2015 ◽  
Vol 139 (5) ◽  
pp. 687-692 ◽  
Author(s):  
Eric Gehrie ◽  
Christopher Tormey
Keyword(s):  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Factor Xa ◽  
Bleeding Risk ◽  
New Drugs ◽  
Laboratory Measurement ◽  
Novel Oral Anticoagulants ◽  
Therapeutic Monitoring ◽  
Thrombin Inhibitor ◽  
Monitoring Process

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

scholarly journals Pharmacogenetics of Direct Oral Anticoagulants

2021 ◽  
Author(s):  
Natalia Shnayder ◽  
Marina Petrova ◽  
Elena Bochanova ◽  
Olga Zimnitskaya ◽  
Alina Savinova ◽  
...  
Keyword(s):  
Vitamin K ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Pharmacokinetic Profile ◽  
Thrombin Inhibitor ◽  
Oral Vitamin ◽  
Treatment And Prevention ◽  
Venous Thromboembolic ◽  
The Individual

For more than 50 years, oral vitamin K antagonists were the choice of anticoagulant for the long-term treatment and prevention of arterial and venous thromboembolic events. In recent years, four direct oral anticoagulants (DOACs), dabigatran, rivaroxaban, apixaban and edoxaban have been compared with warfarin for thromboembolism prevention. These anticoagulants directly inhibit specific proteins within the coagulation cascade; in contrast, oral vitamin K antagonists inhibit the synthesis of vitamin K-dependent clotting factors. Dabigatran, a direct thrombin inhibitor, and rivaroxaban, apixaban and edoxaban, the factor Xa inhibitors, produce a more predictable, less labile anticoagulant effect. DOACs do not have limitations inherent vitamin K antagonists. DOACs have a predictable pharmacokinetic profile and are free of advers drugs reactions inherent in vitamin K antagonists. However, it is necessary to take into account the pharmacogenetic characteristics of the individual that can affect effectiveness and safety of use of DOACs. The results carried out to the present fundamental and clinical studies of DOACs studies demonstrate an undeniable the influence of genome changes on the pharmacokinetics and pharmacodynamics of DOACs. However, the studies need to be continued. There is a need to plan and conduct larger studies in various ethnic groups with the inclusion of sufficient associative genetic studies of the number of patients in each of the documented groups treatments with well-defined phenotypes.

scholarly journals Contribution of novel anticoagulants fondaparinux and dabigatran to venous thromboembolism prevention

2015 ◽  
Vol 143 (3-4) ◽  
pp. 230-236
Author(s):  
Nebojsa Antonijevic ◽  
Vladimir Kanjuh ◽  
Ivana Zivkovic ◽  
Ljubica Jovanovic ◽  
Miodrag Vukcevic ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
North American ◽  
Factor Xa ◽  
Study Groups ◽  
Thrombin Inhibitor ◽  
Vte Prophylaxis ◽  
New Anticoagulants ◽  
Anticoagulant Drugs ◽  
Venous Thromboembolism Prevention

The data that episodes and sequels of venous thromboembolism (VTE) are recorded in a significant percentage of patients receiving standard anticoagulants as VTE prophylaxis (unfractionated, low-molecular-weight heparin and vitamin K inhibitors) as well as the fact that these drugs have significant limitations and that they may cause serious side-effects in some patients indicate the need for the introduction of new anticoagulant drugs. Fondaparinux, a selective inhibitor of Factor Xa, administered following major orthopedic surgeries having a high risk for the development of VTE, is more efficient than enoxaparin sodium used in European and North-American approved doses. The increased incidence of major bleeding (excluding fatal) due to fondaparinux could be perhaps lowered by dosage reduction in patients with a mildly decreased creatinine clearance. Dabigatran, a peroral direct thrombin inhibitor, administered for VTE prophylaxis in elective hip and knee surgery, showed in to date studies the efficacy comparable (if dabigatran is given in both dosage regimes of 150 mg and 220 mg daily) or superior (if dabigatran is given at a dose of 220 mg daily) to enoxaparin administered in European-approved doses, while North American-approved doses of enoxaparin were superior than dabigatran in VTE reduction. No significant differences in bleeding rates were determined in any of the study groups. We consider that the introduction of new anticoagulants, including fondaparinux and dabigatran, will contribute to the establishment of a better safety profile and efficacy, and will also enable adequate therapy individualization for each patient depending on his/hers clinical characteristics. The introduction of novel peroral anticoagulants will, inter alia, significantly contribute to improvement in the quality of life, release the patient from numerous limitations in nutrition, interreaction, frequent laboratory monitoring, and also significantly improve therapeutic predictability.

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