Problem-Based Review: Non Vitamin K Antagonist Oral Anticoagulants for the Acute Physician

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

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Perioperative management of patients receiving non-vitamin K antagonist oral anticoagulants: up-to-date recommendations

Anesthesia and Pain Medicine ◽

10.17085/apm.2020.15.2.133 ◽

2020 ◽

Vol 15 (2) ◽

pp. 133-142

Author(s):

Kwang-Sub Kim ◽

Jong Wook Song ◽

Sarah Soh ◽

Young-Lan Kwak ◽

Jae-Kwang Shim

Keyword(s):

Vitamin K ◽

Clinical Evidence ◽

Oral Anticoagulants ◽

Factor Xa ◽

Bleeding Risk ◽

Vitamin K Antagonist ◽

Thrombin Inhibitor ◽

Reversal Agents ◽

Perioperative Bleeding ◽

Number Of Patients

Indications of non-vitamin K antagonist oral anticoagulants (NOACs), consisting of two types: direct thrombin inhibitor (dabigatran) and direct factor Xa inhibitor (rivaroxaban, apixaban, and edoxaban), have expanded over the last few years. Accordingly, increasing number of patients presenting for surgery are being exposed to NOACs, despite the fact that NOACs are inevitably related to increased perioperative bleeding risk. This review article contains recent clinical evidence-based up-to-date recommendations to help set up a multidisciplinary management strategy to provide a safe perioperative milieu for patients receiving NOACs. In brief, despite the paucity of related clinical evidence, several key recommendations can be drawn based on the emerging clinical evidence, expert consensus, and predictable pharmacological properties of NOACs. In elective surgeries, it seems safe to perform high-bleeding risk surgeries 2 days after cessation of NOAC, regardless of the type of NOAC. Neuraxial anesthesia should be performed 3 days after cessation of NOACs. In both instances, dabigatran needs to be discontinued for an additional 1 or 2 days, depending on the decrease in renal function. NOACs do not require a preoperative heparin bridge therapy. Emergent or urgent surgeries should preferably be delayed for at least 12 h from the last NOAC intake (better if > 24 h). If surgery cannot be delayed, consider using specific reversal agents, which are idarucizumab for dabigatran and andexanet alfa for rivaroxaban, apixaban, and edoxaban. If these specific reversal agents are not available, consider using prothrombin complex concentrates.

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

Stroke Research and Treatment ◽

10.1155/2017/6516401 ◽

2017 ◽

Vol 2017 ◽

pp. 1-4 ◽

Cited By ~ 1

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.

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ORAL ANTICOAGULANTS IN THE TREATMENT OF VENOUS THROMBOEMBOLIC COMPLICATIONS: FOCUS ON APIXABAN

Medical Council ◽

10.21518/2079-701x-2017-7-56-62 ◽

2017 ◽

pp. 56-62 ◽

Cited By ~ 1

Author(s):

M. Yu. Gilyarov ◽

E. V. Konstantinova

Keyword(s):

Vitamin K ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Vitamin K Antagonist ◽

Fixed Dose ◽

Vein Thrombosis ◽

Venous Thromboembolic ◽

Deep Vein

Venous thromboembolism (VTE), comprising deep vein thrombosis and pulmonary embolism, is a common condition associated with a significant clinical and economic burden. Anticoagulant therapy is the mainstay of treatment for VTE. Current guidelines recommend the use of either low molecular weight heparins or fondaparinux overlapping with and followed by a vitamin K antagonist for the initial treatment of VTE, with the vitamin K antagonist continued when long-term anticoagulation is required. These traditional anticoagulants have practical limitations that have led to the development of direct oral anticoagulants that directly target either Factor Xa or thrombin and are administered at a fixed dose without the need for routine coagulation monitoring. The paper reviews results of the trials of apixaban application for treatment and/or long-term secondary prevention of VTE. The paper analyses effectiveness and safety of apixaban in different groups of patients, as well as features of apixaban application in every day practice.

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

Advances in Hematology ◽

10.1155/2015/920361 ◽

2015 ◽

Vol 2015 ◽

pp. 1-19 ◽

Cited By ~ 5

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.

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The NOACs: clinical pharmacology

ESC CardioMed ◽

10.1093/med/9780198784906.003.0056 ◽

2018 ◽

pp. 268-272

Author(s):

Jeffrey Weitz

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Active Site ◽

Randomized Clinical Trials ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Factor Xa ◽

Vitamin K Antagonist ◽

Phase Iii ◽

High Affinity

The limitations of vitamin K antagonists prompted the development of new oral anticoagulants that could be administered in fixed doses without routine coagulation monitoring. Focusing on thrombin and factor Xa because of their prominent roles in coagulation, structure-based design led to the development of small molecules that bind to the active site pockets of these enzymes with high affinity and specificity. Four non-vitamin K antagonist oral anticoagulants are now licensed: dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, and edoxaban, which inhibit factor Xa. In phase III randomized clinical trials that included over 100,000 patients these agents have proven to be at least as effective as vitamin K antagonists for prevention of stroke in patients with non-valvular atrial fibrillation and for treatment of venous thromboembolism, and to produce less bleeding, particularly less intracranial bleeding.

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The Non-Vitamin K Antagonist Oral Anticoagulants in Heart Disease: Section V—Special Situations

Thrombosis and Haemostasis ◽

10.1055/s-0038-1675816 ◽

2018 ◽

Vol 119 (01) ◽

pp. 014-038 ◽

Cited By ~ 10

Author(s):

Raffaele De Caterina ◽

Walter Ageno ◽

Giancarlo Agnelli ◽

Noel Chan ◽

Hans-Christoph Diener ◽

...

Keyword(s):

Clinical Trials ◽

Vitamin K ◽

Oral Anticoagulants ◽

Factor Xa ◽

Risk Profile ◽

Vitamin K Antagonist ◽

The Individual ◽

The Right ◽

Routine Coagulation ◽

Inhibit Factor

AbstractNon-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.

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Patients Taking Direct Oral Anticoagulants (DOAC) Undergoing Oral Surgery: A Review of the Literature and a Proposal of a Peri-Operative Management Protocol

Healthcare ◽

10.3390/healthcare8030281 ◽

2020 ◽

Vol 8 (3) ◽

pp. 281

Author(s):

Saturnino Marco Lupi ◽

Arianna Rodriguez y Baena

Keyword(s):

Vitamin K ◽

Oral Surgery ◽

Dabigatran Etexilate ◽

Oral Anticoagulants ◽

Vitamin K Antagonist ◽

Thrombin Inhibitor ◽

Review Of The Literature ◽

Risk Of Bleeding ◽

Management Protocol ◽

Increased Risk

Patients on anticoagulant therapy for the prevention of cardiovascular accidents present an increased risk of bleeding following dental and oral surgery. Four recently introduced non-vitamin K antagonist oral anticoagulants, namely dabigatran etexilate (direct thrombin inhibitor), rivaroxaban, apixaban, and edoxaban (Xa factor direct inhibitor), are widely spreading for convenience of use compared to the older drug class. Dental management of patients taking these drugs has substantial differences compared to patients on vitamin K antagonist therapy. Anticoagulation is not assessed directly through a hematological test, but indirectly by renal function. The interventions must be scheduled at the time of minimum blood concentration of the drug. Bleeding can occur even after several days following the surgery. The interaction with drugs administered for dental care must be carefully evaluated. The peri-operative diet can influence the risk of bleeding. Local measures favoring coagulation must be adopted. The interventions with higher risk must be divided into multiple less invasive interventions. Although antidotes exist for these drugs, their use does not seem necessary for dental interventions that have been planned optimally. Furthermore, in this review of the literature a decision protocol is proposed for the evaluation of the suspension of the anticoagulant drug before oral surgery. Cessation of any anticoagulant should only be made in consultation with the patient’s general practitioner/cardiologist, who will weigh up the risk of bleeding from the proposed procedure with the risk of thrombosis/stroke in each individual patient.

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An Update on the Reversal of Non-Vitamin K Antagonist Oral Anticoagulants

Advances in Hematology ◽

10.1155/2020/7636104 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Mark Terence P. Mujer ◽

Manoj P. Rai ◽

Varunsiri Atti ◽

Ian Limuel Dimaandal ◽

Abigail S. Chan ◽

...

Keyword(s):

Vitamin K ◽

Oral Anticoagulants ◽

Coagulation Factor ◽

Heart Association ◽

Vitamin K Antagonist ◽

Thrombin Inhibitor ◽

Minor Bleeding ◽

Onset Of Action ◽

Reversal Agents ◽

Andexanet Alfa

Non-vitamin K antagonist oral anticoagulants (NOACs) include thrombin inhibitor dabigatran and coagulation factor Xa inhibitors rivaroxaban, apixaban, edoxaban, and betrixaban. NOACs have several benefits over warfarin, including faster time to the achieve effect, rapid onset of action, fewer documented food and drug interactions, lack of need for routine INR monitoring, and improved patient satisfaction. Local hemostatic measures, supportive care, and withholding the next NOAC dose are usually sufficient to achieve hemostasis among patients presenting with minor bleeding. The administration of reversal agents should be considered in patients on NOAC's with major bleeding manifestations (life-threatening bleeding, or major uncontrolled bleeding), or those who require rapid anticoagulant reversal for an emergent surgical procedure. The Food and Drug Administration (FDA) has approved two reversal agents for NOACs: idarucizumab for dabigatran and andexanet alfa for apixaban and rivaroxaban. The American College of Cardiology (ACC), American Heart Association (AHA), and Heart Rhythm Society (HRS) have released an updated guideline for the management of patients with atrial fibrillation that provides indications for the use of these reversal agents. In addition, the final results of the ANNEXA-4 study that evaluated the efficacy and safety of andexanet alfa were recently published. Several agents are in different phases of clinical trials, and among them, ciraparantag has shown promising results. However, their higher cost and limited availability remains a concern. Here, we provide a brief review of the available reversal agents for NOACs (nonspecific and specific), recent updates on reversal strategies, lab parameters (including point-of-care tests), NOAC resumption, and agents in development.

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Acute phase treatment of VTE: Anticoagulation, including non-vitamin K antagonist oral anticoagulants

Thrombosis and Haemostasis ◽

10.1160/th14-12-1036 ◽

2015 ◽

Vol 113 (06) ◽

pp. 1193-1202 ◽

Cited By ~ 17

Author(s):

Christopher M. Hillis ◽

Mark A. Crowther

Keyword(s):

Acute Phase ◽

Vitamin K ◽

Oral Anticoagulants ◽

Vena Cava ◽

Factor Xa ◽

Bleeding Risk ◽

Vitamin K Antagonist ◽

Risk Scores ◽

Vein Thrombosis ◽

Vena Cava Filters

SummaryThe acute phase of venous thromboembolism (VTE) treatment focuses on the prompt and safe initiation of full-dose anticoagulation to decrease morbidity and mortality. Immediate management consists of resuscitation, supportive care, and thrombolysis for patients with haemodynamically significant pulmonary embolism (PE) or limb-threatening deep-vein thrombosis (DVT). Patients with contraindications to anticoagulants are considered for vena cava filters. Disposition for the acute treatment of VTE is then considered based on published risk scores and the patient's social status, as the first seven days carries the highest risk for VTE recurrence, extension and bleeding due to anticoagulation. Next, a review of: immediate and long-term bleeding risk, comorbidities (i. e. active cancer, renal failure, obesity, thrombophilia), medications, patient preference, VTE location and potential for pregnancy should be undertaken. This will help determine the most suitable anticoagulant for immediate treatment. The non-vitamin K antagonist oral anticoagulants (NOACs), including the factor Xa inhibitors apixaban, edoxaban and rivaroxaban as well as the directthrombin inhibitor dabigatran, are increasing the convenience of and options available for VTE treatment. Current options for immediate treatment include low-molecular-weight heparin (LMWH), unfractionated heparin (UFH), fondaparinux, apixaban, or rivaroxaban. LMWH or UFH may be continued as monotherapy or transitioned to treatment with a VKA, dabigatran or edoxaban. This review describes the upfront treatment of VTE and the evolving role of NOACs in the contemporary management of VTE.

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Spotlight on unmet needs in stroke prevention: The PIONEER AF-PCI, NAVIGATE ESUS and GALILEO trials

Thrombosis and Haemostasis ◽

10.1160/th16-06-0487 ◽

2016 ◽

Vol 116 (S 02) ◽

pp. S33-S40 ◽

Cited By ~ 4

Author(s):

Melanie Hemmrich ◽

Eric Peterson ◽

Karen Thomitzek ◽

Jeffrey Weitz

Keyword(s):

Vitamin K ◽

Stroke Prevention ◽

Therapeutic Option ◽

Oral Anticoagulants ◽

Treatment Strategies ◽

Factor Xa ◽

Vitamin K Antagonist ◽

Phase Iii ◽

Transcatheter Aortic Valve ◽

Randomised Controlled

SummaryAtrial fibrillation (AF) is a major healthcare concern, being associated with an estimated five-fold risk of ischaemic stroke. In patients with AF, anticoagulants reduce stroke risk to a greater extent than acetylsalicylic acid (ASA) or dual antiplatelet therapy (DAPT) with ASA plus clopidogrel. Non-vitamin K antagonist oral anticoagulants (NOACs) are now a widely-accepted therapeutic option for stroke prevention in non-valvular AF (NVAF). There are particular patient types with NVAF for whom treatment challenges remain, owing to sparse clinical data, their high-risk nature or a need to harmonise anticoagulant and antiplatelet regimens if co-administered. This article focuses on three randomised controlled trials (RCTs) that are investigating the utility of rivaroxaban, a direct, oral, factor Xa inhibitor, in additional areas of stroke prevention where data for anticoagulants are lacking: oPenlabel, randomized, controlled, multicentre study explorIng twO treatmeNt stratEgiEs of Rivaroxaban and a dose-adjusted oral vitamin K antagonist treatment (PIONEER AF-PCI); New Approach riVaroxoban Inhibition of factor Xa in a Global trial vs Aspirin to prevenT Embolism in Embolic Stroke of Undetermined Source (NAVIGATE ESUS); and Global study comparing a rivAroxaban-based antithrombotic strategy to an antipLatelet-based strategy after transcatheter aortIc vaLve rEplacement to Optimize clinical outcomes (GALILEO). Data from these studies present collaborative efforts to build upon existing registrational Phase III data for rivaroxaban, driving the need for effective and safe treatment of a wider range of patients for stroke prevention.

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