Continuing Education Activity

Edoxaban belongs to the class of direct oral anticoagulants (DOACs) and is used for the treatment of pulmonary embolism (PE), deep venous thrombosis (DVT), and to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). This drug exerts its therapeutic effects by inhibiting factor Xa directly, selectively, and reversibly as part of its mechanism of action. In contrast to the widely used anticoagulant warfarin, edoxaban offers the advantage of fewer monitoring requirements, lower risk of substantial bleeding, and infrequent drug interactions.

This activity outlines the indications, mechanism of action, and contraindications for edoxaban as a valuable agent in treating and managing thromboembolic events. This activity also highlights the adverse event profile and other crucial considerations related to edoxaban that are essential for healthcare professionals involved in caring for patients with PE, DVT, and NVAF.

Objectives:

• Identify the appropriate patient populations, including those with pulmonary embolism, deep venous thrombosis, and non-valvular atrial fibrillation, who could benefit from edoxaban therapy.
• Screen patients for renal function and creatinine clearance before edoxaban therapy to determine appropriate dosages and assess contraindications.
• Implement appropriate dosing regimens and treatment plans for patients receiving edoxaban to ensure its safe and effective use.
• Communicate with patients effectively about the risks, benefits, and potential adverse effects of edoxaban therapy to facilitate informed decision-making.

Indications

FDA-Approved Indications

Edoxaban belongs to the class of direct oral anticoagulants (DOACs). The U.S. Food and Drug Administration (FDA) approved edoxaban in 2015 for treating deep venous thrombosis (DVT) and pulmonary embolism (PE) following 5 to 10 days of initial therapy with a parenteral anticoagulant. Furthermore, this medication is also used to reduce the risk of hypercoagulability-associated conditions, stroke, and systemic embolism (SE) in individuals with nonvalvular atrial fibrillation (NVAF).[1][2]  Edoxaban is the second once-daily anticoagulant agent approved by the FDA.[3] 

Off-Label Use

Unlike the other DOACs, namely apixaban and rivaroxaban, edoxaban has not obtained FDA approval for secondary and postoperative prophylaxis in venous thromboembolism (VTE) cases.[4]

Edoxaban Compared to Warfarin

Compared to the widely used anticoagulant warfarin, edoxaban offers the advantage of fewer monitoring requirements, lower risk of substantial bleeding, and infrequent drug interactions. Unlike warfarin, edoxaban is minimally affected by the CYP 450 system because it is a minor CYP3A4 substrate.[5] 

Several clinical trials, including the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) and Hokusai-VTE, have highlighted the effectiveness of edoxaban compared to the traditional vitamin K antagonist warfarin. Edoxaban was established as a non-inferior drug compared to warfarin in its ability to prevent the formation of blood clots.[1][5]

Mechanism of Action

Edoxaban exerts its therapeutic effects by inhibiting factor Xa (FXa) directly, selectively, and reversibly as part of its mechanism of action.[5] FXa plays a pivotal role in both the extrinsic and intrinsic pathways of the coagulation cascade. FXa binds with factor Va, creating a complex that facilitates the cleavage of prothrombin into thrombin. Thrombin subsequently cleaves fibrinogen into fibrin monomers and creates a fibrin meshwork, which adheres to a platelet plug and ultimately forms a clot.[6]

By obstructing the active site of free FXa, thrombin production is inhibited, leading to a reduction in thrombus development. This inhibition occurs independently of the anticoagulant effects of cofactor antithrombin III. Edoxaban also functions by inhibiting prothrombinase activity, thereby suppressing thrombin-induced platelet aggregation.

Distribution: Edoxaban has a half-life of 10 to 14 hours and a rapid onset, achieving peak serum concentration levels (Cmax) within 1 to 2 hours.[1]

Elimination: Approximately 50% of the drug is eliminated unchanged through the kidneys and excreted in the urine. The remaining portion undergoes elimination via the biliary and intestinal system, ultimately being excreted in the feces.[1] 

Administration

Dosage Forms and Strengths

Edoxaban is available for oral administration in 15 mg, 30 mg, and 60 mg film-coated tablets. The patient's creatinine clearance (CrCl) should be assessed before initiating the therapy. 

Adult Dosage

Dosing regimens based on indications are as follows:

NVAF: The recommended oral dosage of edoxaban for NVAF is 60 mg once daily, administered to patients with a CrCl >50 and ≤95 mL/min. The dosage should be adjusted to 30 mg once daily for individuals with a CrCl ranging from 15 to 50 mL/min.

Edoxaban is not recommended for patients with NVAF and a CrCl >95 mL/min due to the increased risk of ischemic stroke at the highest studied dose.[7]

DVT: Edoxaban is indicated for the treatment of DVT following 5 to 10 days of initial therapy with a parenteral anticoagulant. The recommended oral dosage is 60 mg, administered to patients once daily. The dosage should be adjusted to 30 mg once daily for patients with CrCl ranging from 15 to 50 mL/min and those with a body weight of less than 60 kg.

PE: Edoxaban is indicated for the treatment of PE following 5 to 10 days of initial therapy with a parenteral anticoagulant. The prescribed oral dosage is 60 mg, administered to patients once daily. The dosage should be adjusted to 30 mg once daily for individuals with CrCl ranging from 15 to 50 mL/min and those with a body weight of less than 60 kg.

Although edoxaban is generally not recommended for concurrent use with specific P-glycoprotein (P-gp) inhibitors, recent studies have indicated that this interaction holds limited clinical significance.[8]

Specific Patient Populations

Hepatic impairment: As per clinicians' recommendations, edoxaban should be avoided in patients with Child-Pugh Class B or C hepatic impairment.

Renal impairment: Thromboembolism or stroke prophylaxis: Edoxaban should be avoided in patients with a CrCl >95 mL/min. No dosage adjustment is necessary for patients with impaired renal function and CrCl ranging from 15 to 30 mL/min. Edoxaban should not be utilized in patients with a CrCl <15 mL/min. Furthermore, edoxaban use should be avoided in individuals undergoing peritoneal dialysis or hemodialysis. 

DVT/PE treatment: If CrCl ranges from 15 to 30 mL/min, the recommended dosage of edoxaban is 30 mg daily. However, edoxaban should be avoided in patients with a CrCl <15 mL/min. Edoxaban use for these indications in patients undergoing peritoneal dialysis or hemodialysis remains undefined.

Pregnancy considerations: As edoxaban is classified as an FDA pregnancy category C drug, its usage should be avoided during pregnancy due to insufficient data from human studies. However, there is no evidence of teratogenicity with the drug's usage.[9] 

Breastfeeding considerations: Clinicians should carefully evaluate the risk-benefit profile when considering breastfeeding patients. Although there is a lack of data from human studies, the drug's pharmaceutical properties may affect its potential to enter breast milk. Research has identified the presence of edoxaban in rat milk. However, no data from human studies are available concerning the drug's effects on milk production.[10][11]

Pediatric patients: Edoxaban is not indicated for use in pediatric patients.

Older patients: For older patients, it is recommended to refer to the renal dosing guidelines.

Adverse Effects

Although edoxaban use is beneficial in preventing thrombotic events, the drug is also associated with a range of potential adverse effects, ranging from severe reactions with profound implications to mild and manageable ones.

Severe Adverse Effects

The severe adverse effects of edoxaban include epidural hematoma, spinal hematoma, severe bleeding, thrombocytopenia, angioedema, and thrombosis with premature discontinuation.

Mild-to-Moderate Adverse Effects

The mild adverse effects of edoxaban include bleeding, anemia, rash, and elevated alanine transaminase or aspartate transaminase.

Early discontinuation of edoxaban without sufficient alternative anticoagulation can increase the risk of ischemic events. If there is no pathological bleeding, transitioning to an alternative agent should be considered.[12] Concurrent administration of edoxaban with other hemostasis-affecting agents, including aspirin, antithrombotics, fibrinolytic drugs, and antiplatelet agents, could amplify the bleeding risk. 

Drug-Drug Interactions

Edoxaban should not be administered concurrently with the following agents due to potential drug interactions and an elevated risk of bleeding:

• Anticoagulants
• Antiplatelets
• Thrombolytics
• Selective serotonin reuptake inhibitors
• Serotonin-norepinephrine reuptake inhibitors
• Defibrotide: Using defibrotide in conjunction with edoxaban may lead to additive effects and an increased risk of bleeding.
• Mifepristone: Combining edoxaban with mifepristone may elevate edoxaban levels, thereby increasing the potential for severe bleeding.

Contraindications

Edoxaban is contraindicated in patients with massive or pathological bleeding. Clinicians should avoid prescribing edoxaban for thromboembolism or stroke prevention in patients with a CrCl >95 mL/min. This drug is not indicated for patients with underlying valvular pathologies or those who have mechanical heart valves.

Patients taking edoxaban and undergoing spinal or epidural puncture procedures are at risk of developing a spinal or epidural hematoma. Indwelling catheters should be paused for a minimum of 12 hours after edoxaban therapy, and the initiation of the drug should be delayed by at least 2 hours after catheter removal. Edoxaban use in patients with moderate-to-severe liver dysfunction is not recommended. 

Box Warnings

• Edoxaban use is associated with reduced efficacy in patients with NVAF with a CrCl of <95 mL/min. Findings from the ENGAGE AF-TIMI 48 trial indicated that individuals with NVAF and a CrCl <95 mL/min displayed a heightened risk of ischemic stroke when taking the daily dosage of 60 mg of edoxaban compared to patients on warfarin. In cases like these, contemplating anticoagulation with an alternative agent is advisable.[5] 

• Premature discontinuation of edoxaban may elevate the risk of ischemic events. If edoxaban use is discontinued for reasons not linked to pathological bleeding or the completion of full therapy duration, transitioning to another anticoagulant agent is recommended. 

• Patients receiving edoxaban and undergoing neuraxial anesthesia or spinal puncture procedures are at risk of developing epidural or spinal hematomas. These hematomas have the potential to lead to extended or even lifelong paralysis. Therefore, before undergoing spinal procedures, it is imperative to carefully weigh the risk-benefit profile associated with edoxaban use.

Monitoring

Patients with renal insufficiency necessitate dosage adjustments in alignment with their kidney function levels. For patients with a glomerular filtration rate (GFR) ranging from 15 to 29 mL/min, the dosage should be reduced by 50%.[1] Renal impairment with a GFR of less than 15 mL/min is a contraindication to edoxaban use.[1] 

A liver function test is recommended initially at baseline, followed by periodic assessments to monitor liver enzyme concentrations. In addition, creatinine levels should be measured to establish a baseline and repeated every 6 to 12 months. However, if the CrCl level is less than 50 in patients, more frequent monitoring at 3-month intervals is recommended.

Edoxaban exerts its effects on both the intrinsic and extrinsic pathway of the coagulation cascade, prolonging clotting tests of both prothrombin time (PT) and activated partial thromboplastin time (aPTT). However, these variations are marginal and do not offer substantial assistance in monitoring the therapeutic effects of edoxaban. An alternative approach is to use the anti-Xa assay to evaluate edoxaban levels. When edoxaban drug concentrations exceed therapeutic levels, the accuracy and reliability of the anti-Xa assay might be compromised.[13]

Toxicity

Patients with impaired kidney function have a higher risk of toxicity. The efficacy of hemodialysis in enhancing edoxaban clearance has not been established. 

Management of Overdose

In cases of overdose or toxicity during bleeding or hemorrhage, general measures can be contemplated, including discontinuing the medication, using mechanical compression, sustaining volume, and replacing hematologic components.[14] Activated charcoal could also be an alternative option if the medication were ingested within the preceding 2 hours.[14] The effects of the agents could potentially endure for up to 24 hours.[15] 

Although no approved or licensed reversal therapy exists for edoxaban, prothrombin complex concentrates (PCCs) are commonly used in pathological bleeding cases.[16] The use of PCCs in bleeding individuals has a minimal logical explanation. Although PCCs replenish clotting factors FII, FVII, and FIX, edoxaban operates downstream of the actions of PCCs within the coagulation cascade.[14][16]. Protamine sulfate, vitamin K, and tranexamic acid are not anticipated to counteract the anticoagulant effects of edoxaban.[16]

Enhancing Healthcare Team Outcomes

Edoxaban is an FDA-approved DOAC indicated for managing VTE and PE and preventing stroke and SE risk in patients with NVAF. The healthcare provider, whether a primary care clinician or specialist, responsible for prescribing the medication should be familiar with the most recent anticoagulation guidelines, clinical trial findings concerning edoxaban, and its indications and potential adverse effects.

Caring for patients with thromboembolic diseases requires a vigilant interprofessional healthcare team to prevent permanent complications and mortality from preventable ischemic events. This interprofessional healthcare team includes a primary care clinician, a hematologist, a cardiologist, a pulmonologist, nurses, and pharmacists. The use of an interprofessional approach is poised to enhance patient outcomes and proactively avert adverse events by coordinating and aligning their efforts and exchanging information as a unified team.

Primary care clinicians and specialists should take the initiative to educate their patients about the potential outcomes of noncompliance with anticoagulant therapy over the entire prescribed duration. Emphasizing the risks of subtherapeutic levels can help patients understand the connection between inadequate dosing and heightened probabilities of thromboembolism and ischemic complications. Before initiating the treatment, the prescriber should establish the patient's baseline liver and kidney function and CrCl levels. This initial assessment is crucial, as dosage adjustments are necessary for individuals with a CrCl of 15 to 50 mL/min. The medication is contraindicated for those with a CrCl <15 mL/min. 

Patients should be provided comprehensive information about the potential common adverse effects of edoxaban therapy, including bleeding risk, rash, and anemia. Regular checkups should be scheduled, and routine monitoring of liver function is essential, as edoxaban treatment might lead to an elevation in liver enzymes. The prescriber of the medication should be aware of the incompatibility of edoxaban with certain P-gp inhibitors. In this scenario, the involvement of a pharmacist in medication reconciliation can prove invaluable. 

Pregnancy requires thorough counseling and vigilant monitoring due to the limited clinical studies on edoxaban's use during pregnancy. Moreover, healthcare providers administering spinal or epidural puncture procedures should exercise caution when dealing with patients on anticoagulants, given the substantial risk of spinal and epidural hematoma, which can lead to permanent impairment. Patients must be thoroughly educated about not using edoxaban concurrently with other hematological agents, as such combinations might heighten the patient's susceptibility to pathological bleeding. Effective interprofessional communication and a shared decision-making approach between healthcare providers and patients are pivotal in cultivating trust and fostering a therapeutic alliance with patients. This approach aids in ensuring patients adhere to therapy, thus minimizing the likelihood of thromboembolism-related complications and achieving the best possible outcomes.

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References

1.

Hurst KV, O'Callaghan JM, Handa A. Risk impact of edoxaban in the management of stroke and venous thromboembolism. Vasc Health Risk Manag. 2016;12:329-35. [PMC free article: PMC4986674] [PubMed: 27563246]

2.

Barrios V, Escobar C. Implications of edoxaban in the prevention and treatment of thromboembolic complications in clinical practice. Future Cardiol. 2016 Jul;12(4):419-33. [PubMed: 27121025]

3.

Guirguis E, Brown D, Grace Y, Patel D, Henningfield S. Establishing Edoxaban's Role in Anticoagulation. J Pharm Pract. 2016 Jun;29(3):228-38. [PubMed: 27169733]

4.

Gibson CM, Finks SW. Edoxaban: How Does the Newest Agent Fit into the DOAC Landscape? Am J Med. 2017 Aug;130(8):900-906. [PubMed: 28390791]

5.

Poulakos M, Walker JN, Baig U, David T. Edoxaban: A direct oral anticoagulant. Am J Health Syst Pharm. 2017 Feb 01;74(3):117-129. [PubMed: 28122753]

6.

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Feb 16, 2023. Edoxaban. [PMC free article: PMC547852] [PubMed: 31644112]

7.

Aursulesei V, Costache II. Anticoagulation in chronic kidney disease: from guidelines to clinical practice. Clin Cardiol. 2019 Aug;42(8):774-782. [PMC free article: PMC6671778] [PubMed: 31102275]

8.

Lenard A, Hermann SA, Stoll F, Burhenne J, Foerster KI, Mikus G, Meid AD, Haefeli WE, Blank A. Effect of Clarithromycin, a Strong CYP3A and P-glycoprotein Inhibitor, on the Pharmacokinetics of Edoxaban in Healthy Volunteers and the Evaluation of the Drug Interaction with Other Oral Factor Xa Inhibitors by a Microdose Cocktail Approach. Cardiovasc Drugs Ther. 2023 Mar 04; [PubMed: 36870039]

9.

Beyer-Westendorf J, Tittl L, Bistervels I, Middeldorp S, Schaefer C, Paulus W, Thomas W, Kemkes-Matthes B, Marten S, Bornhauser M. Safety of direct oral anticoagulant exposure during pregnancy: a retrospective cohort study. Lancet Haematol. 2020 Dec;7(12):e884-e891. [PubMed: 33242445]

10.

Drugs and Lactation Database (LactMed®) [Internet]. National Institute of Child Health and Human Development; Bethesda (MD): Jul 15, 2023. Edoxaban. [PubMed: 29999799]

11.

Daei M, Khalili H, Heidari Z. Direct oral anticoagulant safety during breastfeeding: a narrative review. Eur J Clin Pharmacol. 2021 Oct;77(10):1465-1471. [PubMed: 33963877]

12.

Minor C, Tellor KB, Armbruster AL. Edoxaban, a Novel Oral Factor Xa Inhibitor. Ann Pharmacother. 2015 Jul;49(7):843-50. [PubMed: 25855704]

13.

Cuker A, Husseinzadeh H. Laboratory measurement of the anticoagulant activity of edoxaban: a systematic review. J Thromb Thrombolysis. 2015 Apr;39(3):288-94. [PMC free article: PMC4608015] [PubMed: 25669624]

14.

Keeling D, Cotter F. Management of bleeding in patients taking FXa and FIIa inhibitors. Br J Haematol. 2013 Jan;160(1):1-2. [PubMed: 23110431]

15.

Camm AJ, Bounameaux H. Edoxaban: a new oral direct factor xa inhibitor. Drugs. 2011 Aug 20;71(12):1503-26. [PubMed: 21861537]

16.

Levy JH, Douketis J, Weitz JI. Reversal agents for non-vitamin K antagonist oral anticoagulants. Nat Rev Cardiol. 2018 May;15(5):273-281. [PubMed: 29345686]

Disclosure: Inderbir Padda declares no relevant financial relationships with ineligible companies.

Disclosure: Yuvraj Chowdhury declares no relevant financial relationships with ineligible companies.