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

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

Acute Medicine Journal ◽

10.52964/amja.0435 ◽

2015 ◽

Vol 14 (2) ◽

pp. 83-89

Author(s):

Jecko Thachil ◽

◽

James Gagg ◽

Keyword(s):

Vitamin K ◽

Oral Anticoagulants ◽

Factor Xa ◽

Coagulation Factors ◽

Rapid Onset ◽

Vitamin K Antagonist ◽

Thrombin Inhibitor ◽

Oral Formulations ◽

Direct Anticoagulants ◽

And Function

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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Reversal of oral anticoagulants

ESC CardioMed ◽

10.1093/med/9780198784906.003.0058 ◽

2018 ◽

pp. 278-281

Author(s):

Joanne van Ryn

Keyword(s):

Clinical Trials ◽

Vitamin K ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Coagulation Factor ◽

Vitamin K Antagonist ◽

Reversal Agent ◽

Reversal Agents ◽

Trial Testing

Oral anticoagulation reduces the risk of stroke in patients with atrial fibrillation and is effective in treating or preventing thromboembolic events. These indications have been the mainstay of vitamin K antagonist therapy for decades; however, in recent years a number of direct oral anticoagulants have also been approved for these indications. They circumvent many of the disadvantages associated with vitamin K antagonist use; however, the lack of a rapid and safe reversal strategy in emergency settings is often considered a hurdle to their more widespread use. Historically, coagulation factor concentrates have been used for rapid vitamin K antagonist reversal, though evidence from clinical trials has only been established in recent years. In addition, several new approaches to the specific reversal of anticoagulation have been developed. The first of these, idarucizumab, a specific reversal agent for dabigatran, was approved in 2015. A specific reversal agent for the factor Xa inhibitors, andexanet alfa, is currently in clinical trial testing, and a further compound, ciraparantag, is undergoing testing in healthy volunteers. This chapter discusses the mechanism of action of these reversal agents, their target anticoagulants, and the most recent data available in both volunteer and clinical trials.

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Direct Oral Anticoagulants

10.2310/7ccsp.8343 ◽

2017 ◽

Author(s):

Panna A. Codner ◽

Michael G Mount

Keyword(s):

Perioperative Management ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Vitamin K Antagonist ◽

Direct Thrombin Inhibitor ◽

Thrombin Inhibitor ◽

Clinical Use ◽

Nonvalvular Atrial Fibrillation ◽

Reversal Agents

Non–vitamin K antagonist oral anticoagulants, also known as direct oral anticoagulants, are a relatively recent class of medications introduced into clinical practice. Due to their safety profiles, fixed dosing, and lack of need for frequent laboratory monitoring, they are becoming preferred to traditional anticoagulation with warfarin in many cases of nonvalvular atrial fibrillation and venous thromboembolism. Currently, four drugs are available: dabigatran, a direct thrombin inhibitor, and rivaroxaban, apixaban, and edoxaban, factor Xa inhibitors. This review covers the pharmacology, monitoring, and reversal agents currently available for these medications. The indications for their use are covered through a review of the major clinical trials that led to their US and European approvals for clinical use. Perioperative management of these medications is discussed. Tables list indications, dosing, and monitoring, as well as bleeding risks and efficacy compared with warfarin. This review contains 1 figure, 11 tables, and 70 references. Key words: apixaban, dabigatran, direct oral anticoagulant, edoxaban, rivaroxaban

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Perioperative Management of Patients Receiving New Anticoagulants

Current Pharmaceutical Design ◽

10.2174/1381612825666190709220449 ◽

2019 ◽

Vol 25 (19) ◽

pp. 2149-2157 ◽

Cited By ~ 1

Author(s):

Massimo Lamperti ◽

Andrey Khozenko ◽

Arun Kumar

Keyword(s):

Vitamin K ◽

Elective Surgery ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Oral Intake ◽

Bleeding Risk ◽

Dietary Vitamin ◽

Reversal Agent ◽

Onset Of Action ◽

Reversal Agents

There is an increased use of oral anticoagulants for the prevention of venous and arterial thrombosis. Vitamin-K antagonists have been used for decades as the main oral anticoagulants but they have the draback a complex therapeutic management, slow onset of action and by a different oral intake caused by dietary vitamin K intake. New non-vitamin K antagonist oral anticoagulants (NOACs) have been developed to overcome the limitations of warfarin. Their management is easier as it requires a fixed daily dose without coagulation monitoring. Although their therapeutic profile is safe, proper attention should be paid in case of unexpected need for the reversal of their coagulation effect and in case a patient needs to have a scheduled surgery. For non-acute cardiac surgery, discontinuation of NOACs should start at least 48 hours prior surgery. Intracranial bleedings associated with NOACs are less dangerous comparing to those warfarin-induced. NOACs need to be stopped ≥24 hours in case of elective surgery for low bleeding-risk procedures and ≥48 hours for high bleeding-risk surgery in patients with normal renal function and 72 hours in case of reduced CrCl < 80. The therapy with NOACs should be resumed from 48 to 72 hours after the procedure depending on the perceived bleeding, type of surgery and thrombotic risks. There are some available NOAC reversal agents acting within 5 to 20 minutes. In case of lack of reversal agent, adequate diuresis, renal replacement therapy and activated charcoal in case of recent ingestion should be considered.

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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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HEMATURIA AND OTHER KINDS OF BLEEDINGS ON NON-VITAMIN K ANTAGONIST ORAL ANTICOAGULANTS IN PATIENTS WITH ATRIAL FIBRILLATION: AN UPDATED OVERVIEW ON OCCURRENCE, PATHOMECHANISMS AND MANAGEMENT

Wiadomości Lekarskie ◽

10.36740/wlek202011135 ◽

2020 ◽

Vol 73 (11) ◽

pp. 2528-2534

Author(s):

Dagmara Wojtowicz ◽

Anna Tomaszuk-Kazberuk ◽

Jolanta Małyszko ◽

Marek Koziński

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Anticoagulant Activity ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Vitamin K Antagonist ◽

Bleeding Complications ◽

Reversal Agents ◽

Limited Availability ◽

Increased Risk

Non-vitamin K antagonist oral anticoagulants (NOACs) are currently recommended for oral anticoagulation in patients with non-valvular atrial fibrillation. In the setting, NOACs effectively prevent from stroke and systemic embolic events. In spite of the favorable safety profile of NOACs when compared with vitamin K antagonists, the use of any kind of anticoagulation is associated with an increased risk of bleeding. However, there is still a lack of direct comparisons of effectiveness and safety among NOACs. The results of indirect comparisons and meta-analyses suggest that the risk of various types of hemorrhagic complications differ among the particular NOACs. Management of bleeding in patients under NOAC therapy can be challenging because of limited availability of antidotes and the lack of routine laboratory test monitoring the NOAC anticoagulant effect. In case of life-threatening or critical site bleeding, reversal of NOAC anticoagulant activity is essential together with immediate implementation of causative treatment. Moreover, some patients on chronic NOAC therapy may require urgent surgery or invasive procedures. Specific reversal agents for NOACs have been developed, i.e. more widely available idarucizumab for the factor IIa inhibitor (dabigatran) and andexanet alfa for the factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) with limited availability. This review summarizes the occurrence and management of NOAC-related bleeding complications with a particular emphasis on hematuria.

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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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