Continuing Education Activity

Edoxaban is a medication used in the management and treatment of pulmonary embolism (PE), deep venous thrombosis (DVT), and non-valvular atrial fibrillation (NVAF). It is in the direct-acting oral anticoagulant class of drugs. This activity outlines the indications, action, and contraindications for edoxaban as a valuable agent in treating and managing thromboembolic events. This activity will highlight the mechanism of action, adverse event profile, and other key factors pertinent to the healthcare team members in caring for patients with pulmonary embolism, deep venous thrombosis, and non-valvular atrial fibrillation.

Objectives:

• Identify the mechanism of action of edoxaban.
• Summarize the most common adverse events associated with edoxaban therapy.
• Describe the contraindications to using edoxaban.
• Outline some interprofessional team strategies for improving care coordination and communication to patients receiving edoxaban therapy.

Indications

Edoxaban is a direct oral anticoagulant (DOAC). It exerts its effects by inhibiting factor Xa (FXa). Edoxaban was FDA approved in early 2015 to treat deep venous thrombosis, pulmonary embolism and decrease the risk of hypercoagulability-related illness, stroke, and systemic embolism (SE) in subjects with nonvalvular atrial fibrillation (NVAF).[1][2] Compared to the popularly used anticoagulant warfarin, edoxaban entails a reduced need for monitoring and possesses a reduced risk for significant bleeding and fewer interactions with other agents.[3] Edoxaban is the most current direct oral anticoagulant (DOAC) and does not associate with the CYP-450 system.[3] 

Various clinical trials and studies (ENGAGE AF-TIMI and Hokusai-VTE) expressed edoxaban's effectiveness compared to the conventional vitamin K antagonist warfarin. It was demonstrated to be non-inferior in preventing blood clots compared to warfarin.[1][3] Edoxaban is the second FDA-approved anticoagulant agent with once-daily administration.[4] Contrary to the other direct oral anticoagulants, apixaban and rivaroxaban, edoxaban has not yet received approval for secondary and postoperative prophylaxis for venous thromboembolism (VTE).[5]

FDA-Approved Indications

• Deep venous thrombosis
• Pulmonary embolism
• Nonvalvular atrial fibrillation (NVAF)

Mechanism of Action

Edoxaban exerts its mechanism of action via direct, reversible, selective inhibition of factor Xa.[3] Factor Xa works on both the extrinsic and intrinsic pathways of the coagulation cascade. Factory Xa binds factor Va forming a complex which functions to separate prothrombin from thrombin. Thrombin further divides fibrinogen into fibrin monomers, creating a fibrin meshwork that adheres to a platelet plug producing a clot.[6] The inhibition of free factor Xa inhibits thrombin production and lessens thrombus development without co-factor antithrombin III exerting its anticoagulant effects. Edoxaban also functions to hinder prothrombinase activity and restrains thrombin-induced platelet aggregation.

Administration

Edoxaban is available for oral administration in three dosage forms and strengths

• 15 mg 
• 30 mg 
• 60 mg 

Nonvalvular Atrial Fibrillation

• 60 mg orally administered once a day

Dosage should be modified and decreased to 30mg once a day in subjects with CrCL 15 to 50 mL/min.

Deep Vein Thrombosis

• 60 mg orally administered once a day 

Dosage should be modified and decreased to 30mg once a day in subjects with CrCL 15 to 50 mL/min and patients weighing <60kg.

Pulmonary Embolism

• 60 mg orally administered once a day

Dosage should be modified and decreased to 30mg once a day in subjects with CrCL 15 to 50 mL/min and patients weighing <60kg.

Adverse Effects

• Risk of Bleeding
• Rash
• Anemia
• Abnormal liver function tests
• Interstitial lung disease (ILD)

Early stoppage of edoxaban and the lack of sufficient alternative anticoagulation can increase the risk of ischemic events. Transitioning to another agent should be considered in the absence of pathological bleeding.[7] The concurrent use of edoxaban with other agents affecting hemostasis, such as aspirin, antithrombotics, fibrinolytic drugs, and antiplatelet agents, may increase the bleeding risk. 

Contraindications

Edoxaban is contraindicated in patients with massive or pathological bleeding. Edoxaban should also not be used to manage patients with CrCL higher than 95 mL/min. The ENGAGE AFTIMI 48 study demonstrated that subjects with nonvalvular atrial fibrillation patients and CrCL higher than 95 mL/min had a more significant risk of ischemic stroke with a 60 mg daily dosage of edoxaban compared to subjects managed with warfarin.[3] 

Edoxaban is not for patients with underlying valvular pathologies or patients with mechanical heart valves. Patients taking edoxaban and undergoing spinal or epidural puncture procedures are at risk of producing a spinal or epidural hematoma. Indwelling catheters should be held for at least 12 hours post edoxaban therapy, and the agent should not be started for at least two hours post catheter removal.

Monitoring

Edoxaban has a half-life of 10 to 14 hours and a fast onset with serum concentration levels peaking at 1 to 2 hours (Cmax).[1] About 50% of the drug is cleared through the kidneys in unchanged form and excreted in the urine.[1] The remainder is eliminated through the biliary and intestinal system and excreted through feces[1]. Patients with renal insufficiency should have dosages adjusted according to kidney function levels. Patients with a GFR of 15 to 29 mL/min should have decreased dosage by 50%.[1] Renal impairment with a GFR less than 15 mL/min is a contraindication to edoxaban.[1] Edoxaban exerts its effects on 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 minor and not useful in monitoring edoxaban's therapeutic effects.

Pregnancy Category C: edoxaban should be used with caution only if benefits outweigh risks as there haven't been enough studies during pregnancy.

Toxicity

Patients with impaired kidney function have a higher risk of toxicity. No distinct agent for reversal as yet exists, and agents such as protamine sulfate, vitamin K, and tranexamic acid have not demonstrated effectiveness.[8] Hemodialysis has not proven to increase the clearance of edoxaban. Vague measures can be considered in the event of overdose/toxicity during a bleed or hemorrhage, such as suspending the agent, mechanical compression, sustaining volume, and replacing hematologic components.[9]

If the agent was administered within the past 2 hours, activated charcoal could also be an alternative.[9] The effects of the agents may persist for up to 24 hours.[10] Although no indicated reversal therapy for edoxaban has been approved or licensed, prothrombin complex concentrates (PCC) are frequently used in subjects presenting with pathological bleeding.[8] The use of PCC in bleeding individuals has a minor logical explanation. Clotting factors Fll, FVll, and FlX, are restored with PCC, but edoxaban exerts its effects below the action of PCC in the coagulation cascade.[9][8]

Enhancing Healthcare Team Outcomes

Edoxaban is a direct oral anticoagulant (DOAC) that is FDA-approved and indicated for the treatment of venous thromboembolism (VTE), pulmonary embolism (PE), and to decrease the risk of stroke and systemic embolism (SE) for patients with nonvalvular atrial fibrillation (NVAF). The primary care clinician or specialist prescribing the drug should be up to date on the latest anticoagulation guidelines and the latest clinical trial studies on edoxaban and its indication and adverse effects. The care for patients with thromboembolic diseases prompts critical care from an interprofessional team of healthcare professionals as preventable ischemic events can lead to life-long permanent complications and mortality. These healthcare professionals include a primary care clinician, a hematologist, a cardiologist, a pulmonologist, a nurse, and a pharmacist coordinating their activities and sharing information as a cohesive interprofessional team. This interprofessional approach will drive better patient outcomes and help to preclude adverse events. [Level 5]

The primary care clinicians and specialists should educate their patients about the consequences of non-compliance with anticoagulant therapy for the full duration and how subtherapeutic levels can further result in thromboembolism and ischemic complexities. Before initiating therapy, the prescribing physician should be aware of the kidney function and CrCL levels, as dosing modifications are required for CrCL 15 to 50 mL/min and contraindicated in CrCL <15 mL/min. Patients should receive information on the common adverse effects that may occur while on therapy with edoxaban, such as the risk of bleeding, rash, and anemia. Routine check-ups should be scheduled, and liver functions monitored routinely as edoxaban therapy may cause an elevation in liver enzymes.

Counseling and careful monitoring should be conducted during pregnancy, as clinical studies during its use in pregnancy are limited, and edoxaban is labeled as pregnancy category C. The clinician performing spinal or epidural puncture procedures should be aware of patients currently taking anticoagulants as there is a significant risk for spinal and epidural hematoma, which can cause life-long impairment. The patient should also be fully informed of no concurrent use with other hematologic agents as it may predispose the patient to an increased risk of pathological bleeding. Interprofessional communication is key to building patient rapport and developing a therapeutic alliance, so the patients comply with therapy adequately to prevent thromboembolism-related complications.