Can edoxaban (Savaysa) be given to a patient with impaired renal function and atrial fibrillation (AF) with a creatinine clearance (CrCl) of 39?

Can Edoxaban Be Given in This Patient?

Yes, edoxaban can be given to this 60-year-old man with atrial fibrillation and CrCl of 39 mL/min, but the dose must be reduced to 30 mg once daily. 1

Dosing Algorithm for Edoxaban Based on Renal Function

Standard Dose (60 mg once daily)

• CrCl >50 to ≤95 mL/min: Use edoxaban 60 mg once daily 1
• CrCl >95 mL/min: Consider alternative anticoagulants due to decreased relative efficacy compared to warfarin 1, 2

Reduced Dose (30 mg once daily) - Applies to Your Patient

• CrCl 30-50 mL/min: Reduce dose to 30 mg once daily 1
• Body weight ≤60 kg: Reduce dose to 30 mg once daily 1
• Concomitant use of potent P-glycoprotein inhibitors: Reduce dose to 30 mg once daily 1

Contraindications

• CrCl <15 mL/min or dialysis-dependent: Edoxaban is not recommended 1
• CrCl 15-29 mL/min (Stage 4 CKD): Edoxaban 15 mg once daily is approved in Europe but use with extreme caution; limited evidence exists 1

Why Edoxaban Is Appropriate for This Patient

Your patient with CrCl 39 mL/min falls into the moderate renal impairment category (CrCl 30-50 mL/min), which requires dose reduction to 30 mg once daily. 1

Pharmacokinetic Rationale

• Edoxaban has 50% renal clearance, making it intermediate among NOACs 1
• The dose reduction to 50% (30 mg) is applied more rapidly than with rivaroxaban and was tested in a large subgroup of the ENGAGE AF-TIMI 48 trial 1, 2
• In patients with CrCl 30-50 mL/min, edoxaban 30 mg daily demonstrated similar efficacy to warfarin for stroke/systemic embolism prevention with lower bleeding rates 3, 2

Evidence from Clinical Trials

• The ENGAGE AF-TIMI 48 trial showed that edoxaban with dose reduction maintained consistent efficacy and safety across the range of renal function 2
• Meta-analysis data confirm that edoxaban 30 mg daily in patients with CrCl 30-50 mL/min results in lower bleeding rates (HR 0.75,95% CI 0.60-0.93) and better net clinical outcomes (HR 0.75,95% CI 0.63-0.90) compared to warfarin 3

Monitoring Requirements

Renal function must be monitored more frequently in patients with impaired kidney function. 1

Monitoring Schedule

• General rule: Divide CrCl by 10 to obtain minimum frequency of testing in months 1
• For CrCl 39 mL/min: Monitor renal function approximately every 4 months 1
• More frequent monitoring if patient has additional risk factors (older age, frail, multiple comorbidities, intercurrent acute illness) 1

Method of Assessment

• Use Cockcroft-Gault equation to calculate CrCl, as this was used in NOAC trials 1
• Do not confuse chronic kidney disease with acute renal failure; in acute situations, discontinue NOACs and use parenteral anticoagulation 1

Comparison to Alternative Anticoagulants

Why Not Other NOACs?

• Dabigatran: 80% renal clearance makes it less favorable in renal impairment; requires 75 mg BID in US for CrCl 15-30 mL/min (not approved in Europe for this indication) 1
• Rivaroxaban: 35% renal clearance; dose reduced by only 25% (to 15 mg daily) for CrCl 30-50 mL/min 1
• Apixaban: 27% renal clearance (lowest among NOACs); however, dose reduction requires meeting 2 of 3 criteria (age ≥80, weight ≤60 kg, creatinine ≥1.5 mg/dL), not solely based on CrCl 1, 4

Edoxaban Advantages in Moderate Renal Impairment

• Clear dose reduction algorithm based on CrCl alone 1
• 50% dose reduction provides appropriate drug exposure in renal impairment 1, 2
• Demonstrated safety in patients with CrCl 30-50 mL/min with lower bleeding rates than warfarin 3, 2

Critical Pitfalls to Avoid

Do Not Use Standard Dose

• Never use 60 mg daily in patients with CrCl 30-50 mL/min; this is the most common prescribing error 5
• Studies show inappropriate dosing occurs in 60.8% of cases, particularly in patients with renal insufficiency 5

Avoid in Supranormal Renal Function

• CrCl >95 mL/min: FDA issued warning about decreased efficacy of edoxaban 60 mg compared to warfarin in this population 1, 2
• Consider alternative anticoagulants if CrCl >95 mL/min 1

Watch for Acute Renal Deterioration

• Intercurrent acute illness (infections, acute heart failure) may transiently affect renal function and require re-evaluation 1
• Patients should be instructed to contact healthcare provider during acute illnesses 1

Drug Interactions

• Concomitant P-glycoprotein inhibitors may require additional dose adjustment or avoidance 1
• Edoxaban is a P-glycoprotein substrate; strong inhibitors increase drug levels 1

Clinical Outcomes Data

Real-world evidence supports the safety and efficacy of edoxaban 30 mg in moderate renal impairment. 3, 6

• Retrospective studies show no major bleeding or thrombotic events in patients with severe CKD treated with edoxaban 30 mg daily 6
• Net clinical outcome is superior with edoxaban compared to warfarin across various CrCl groups 3
• The relative risk reduction for bleeding is preserved across all levels of renal function 2