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Sunday, July 27, 2025

Edoxaban


Edoxaban is a selective oral anticoagulant belonging to the class of direct oral factor Xa inhibitors (DOACs). It is used in the prevention and treatment of thromboembolic disorders such as stroke prevention in non-valvular atrial fibrillation (NVAF), deep vein thrombosis (DVT), and pulmonary embolism (PE). It acts by directly inhibiting factor Xa, an essential component in the blood coagulation cascade, thereby reducing the generation of thrombin and thrombus formation.

Pharmacological Classification

  • Therapeutic class: Antithrombotic / Anticoagulant

  • Pharmacologic class: Selective direct Factor Xa inhibitor (DOAC)

  • ATC code: B01AF03

  • Available formulation: Oral tablets (15 mg, 30 mg, 60 mg)

  • Brand name: Lixiana (EU, UK, Asia), Savaysa (USA)

  • Legal classification: Prescription only (Rx)

Mechanism of Action

Edoxaban selectively and reversibly inhibits factor Xa, an enzyme pivotal in the conversion of prothrombin to thrombin in both intrinsic and extrinsic coagulation pathways. This inhibition:

  • Reduces thrombin formation

  • Suppresses fibrin clot development

  • Minimally affects platelet function (unlike heparin)

Unlike vitamin K antagonists (e.g., warfarin), edoxaban exerts its anticoagulant effect without the need for routine INR monitoring, and it has a rapid onset and offset of action.

Approved Indications

1. Prevention of Stroke and Systemic Embolism

  • In adults with non-valvular atrial fibrillation (NVAF) and at least one additional risk factor (e.g., prior stroke or TIA, age ≥75 years, hypertension, diabetes, heart failure)

2. Treatment and Secondary Prevention of Venous Thromboembolism (VTE)

  • Includes deep vein thrombosis (DVT) and pulmonary embolism (PE)

  • Following 5 days of initial treatment with a parenteral anticoagulant (e.g., LMWH)

3. Prevention of VTE following orthopedic surgery (in some countries, off-label in others)

Dosage and Administration

Non-valvular Atrial Fibrillation

  • Standard dose: 60 mg once daily

  • Reduced dose: 30 mg once daily if:

    • CrCl 15–50 mL/min

    • Body weight ≤60 kg

    • Concomitant use with P-gp inhibitors (e.g., dronedarone, verapamil, quinidine)

Treatment of DVT/PE

  • Initiate after 5 days of parenteral anticoagulant

  • Standard dose: 60 mg once daily

  • Reduced dose: 30 mg once daily under same criteria as above

Renal Impairment

  • Avoid use if CrCl <15 mL/min

  • Adjust dose for moderate impairment (15–50 mL/min) to 30 mg

Hepatic Impairment

  • Avoid in moderate to severe hepatic impairment

  • Not recommended in elevated liver enzymes (>2x ULN) or liver disease associated with coagulopathy

Pharmacokinetics

  • Bioavailability: ~62%

  • Time to peak plasma concentration: 1–2 hours

  • Half-life: 10–14 hours

  • Protein binding: ~55%

  • Metabolism: Minimal CYP3A4 involvement; metabolized primarily via hydrolysis and conjugation

  • Excretion: ~50% renal; remainder fecal

Contraindications

  • Active major bleeding

  • Severe renal impairment (CrCl <15 mL/min)

  • Moderate-to-severe hepatic disease with coagulopathy

  • Uncontrolled hypertension

  • Mechanical prosthetic heart valves

  • Concomitant treatment with other anticoagulants (unless switching or bridging)

  • Pregnancy and breastfeeding (due to lack of safety data)

  • Hypersensitivity to edoxaban or any of its components

Warnings and Precautions

Bleeding Risk

  • Risk of major and fatal bleeding including:

    • Intracranial hemorrhage

    • Gastrointestinal bleeding

  • Risk increased with concurrent use of antiplatelets, NSAIDs, SSRIs/SNRIs

  • Monitor signs of bleeding and discontinue if life-threatening

Spinal/Epidural Hematoma

  • Risk increased in patients undergoing neuraxial anesthesia or spinal puncture

  • Can lead to long-term or permanent paralysis

  • Delay administration after catheter removal as per guidelines

Renal Function

  • Monitor renal function at baseline and during therapy

  • Renal function affects dosing

Liver Impairment

  • Not recommended in patients with hepatic disease associated with coagulopathy

  • Liver enzymes should be monitored

Use in Underweight Patients

  • Patients ≤60 kg require dose reduction due to increased plasma levels

Adverse Effects

Common (≥1%)

  • Bleeding events (e.g., epistaxis, hematuria, GI bleeding)

  • Anemia

  • Nausea

  • Rash

  • Elevated liver enzymes (ALT, AST)

Uncommon to Rare

  • Intracranial hemorrhage

  • Spinal hematoma (with neuraxial anesthesia)

  • Thrombocytopenia

  • Hypersensitivity reactions

  • Hepatotoxicity (rare)

Drug Interactions

Increased Bleeding Risk

  • Antiplatelet agents: Aspirin, clopidogrel

  • NSAIDs

  • SSRIs/SNRIs

  • Other anticoagulants: Avoid unless transitioning

P-glycoprotein (P-gp) Inhibitors

  • Reduce dose to 30 mg daily if used concurrently with:

    • Verapamil

    • Quinidine

    • Dronedarone

    • Erythromycin

  • Avoid use with potent P-gp inducers (e.g., rifampin, phenytoin, carbamazepine, St. John’s Wort) due to reduced efficacy

CYP450

  • Minimal CYP3A4 metabolism; fewer interactions than warfarin

Monitoring Parameters

  • No routine coagulation monitoring required (unlike warfarin)

  • Check renal function at baseline and periodically

  • Hepatic enzymes if history of liver disease

  • Clinical monitoring for signs of bleeding

  • CBC, including hemoglobin and hematocrit, periodically

Use in Special Populations

Pregnancy

  • Contraindicated; may cause fetal bleeding and teratogenicity

Breastfeeding

  • Excretion in human milk unknown; not recommended

Elderly

  • No routine dose adjustment; monitor renal function and bleeding risk

Pediatrics

  • Not approved for use in children

Obesity

  • Use with caution in BMI >40 kg/m² or weight >120 kg; limited data

Reversal of Anticoagulant Effect

  • No specific antidote for edoxaban (as of early 2025)

  • Andexanet alfa (approved for rivaroxaban/apixaban) may have off-label utility

  • Supportive care in bleeding: activated charcoal (if recent), prothrombin complex concentrate (PCC), blood products

Clinical Trial Evidence

ENGAGE AF-TIMI 48 Trial (2013)

  • In 21,105 patients with NVAF:

    • Edoxaban non-inferior to warfarin in preventing stroke/systemic embolism

    • Significantly lower rates of major bleeding and CV mortality

Hokusai-VTE Trial (2013)

  • In patients with DVT/PE:

    • Edoxaban non-inferior to warfarin in preventing recurrent VTE

    • Reduced risk of bleeding complications

Comparison with Other DOACs

  • Apixaban: Lower bleeding risk in some studies; preferred in elderly with high bleeding risk

  • Rivaroxaban: Once-daily dosing also; more GI bleeding reported

  • Dabigatran: Direct thrombin inhibitor; higher GI side effects and BID dosing

  • Edoxaban: Simpler renal adjustment criteria; fewer CYP450 interactions

Patient Counseling Points

  • Take once daily, with or without food (preferably same time each day)

  • Do not skip doses; compliance is critical

  • Inform all healthcare providers (including dentists) of anticoagulant use

  • Monitor for signs of bleeding: unusual bruising, prolonged bleeding, blood in stool/urine

  • Avoid NSAIDs, and caution with alcohol

  • Do not stop abruptly unless advised by a healthcare professional

  • Store at room temperature, away from moisture



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