How does impaired renal function, as indicated by a lower estimated Glomerular Filtration Rate (eGFR), affect the dosage of Apixaban (apixaban)?

Apixaban Dosing Based on eGFR

For patients with normal to moderate renal impairment (eGFR ≥30 mL/min), use apixaban 5 mg twice daily, reducing to 2.5 mg twice daily only if the patient meets at least 2 of 3 criteria: age ≥80 years, weight ≤60 kg, or serum creatinine ≥1.5 mg/dL. 1, 2

Dosing Algorithm by Renal Function

eGFR >50 mL/min (Normal to Mild Impairment)

• Standard dose: 5 mg twice daily with no renal-based adjustment required 1, 2
• Apply dose reduction criteria only if ≥2 of the following are present: age ≥80 years, weight ≤60 kg, or serum creatinine ≥1.5 mg/dL 1, 2

eGFR 30-50 mL/min (Moderate Impairment/CKD Stage 3)

• Standard dose: 5 mg twice daily remains appropriate 1, 2
• Reduce to 2.5 mg twice daily if patient meets ≥2 dose reduction criteria (age ≥80 years, weight ≤60 kg, or serum creatinine ≥1.5 mg/dL) 1, 2
• This recommendation is supported by high-quality RCT data from the ARISTOTLE trial involving 18,201 patients 1, 3

eGFR 15-29 mL/min (Severe Impairment/CKD Stage 4)

• Reduce dose to 2.5 mg twice daily 2
• This recommendation relies on FDA/EMA regulatory approval and pharmacokinetic modeling, as RCTs excluded these patients 2
• Apixaban has the lowest renal clearance (27%) among all DOACs, making it the most favorable option in severe renal impairment 2, 4

eGFR <15 mL/min or End-Stage Renal Disease on Dialysis

• Use apixaban 5 mg twice daily for stable hemodialysis patients 1, 5
• Reduce to 2.5 mg twice daily if age ≥80 years OR weight ≤60 kg 1, 5
• Pharmacokinetic data show that 2.5 mg twice daily in dialysis patients produces drug exposure comparable to 5 mg twice daily in patients with normal renal function 1, 5
• Observational data from 25,523 dialysis patients showed standard-dose apixaban (5 mg twice daily) was associated with lower risk of stroke/embolism and death compared to reduced-dose apixaban and warfarin 5

Critical Monitoring Requirements

• Use the Cockcroft-Gault equation for dosing decisions, as this was used in pivotal trials 1, 2
• Renal function should be evaluated before initiation and reassessed at least annually, or more frequently if clinical deterioration occurs 1, 2
• Monitor more frequently in patients with eGFR 30-50 mL/min or declining renal function 1

Pharmacokinetic Rationale

• Apixaban has 27% renal clearance, the lowest among all DOACs 1, 2, 4
• By comparison: dabigatran (80%), rivaroxaban (66%), edoxaban (50%) 1
• Apixaban is metabolized mainly via CYP3A4 with minor contributions from other enzymes 4
• Approximately 25% of an oral dose is recovered in urine and feces as metabolites 4

Evidence Quality and Safety Data

• Dosing recommendations for eGFR >30 mL/min are based on high-quality RCT data from ARISTOTLE 1, 3
• In the ARISTOTLE trial, apixaban was more effective than warfarin in preventing stroke and reducing mortality irrespective of renal function 3
• The relative risk reduction in major bleeding was greater in patients with eGFR ≤50 mL/min (HR 0.50,95% CI 0.38-0.66) 3
• A 2024 Danish registry study of 26,686 patients found apixaban was associated with 21% lower relative risk of major bleeding compared to warfarin, with even greater risk reduction in patients with eGFR 15-30 mL/min 6
• Meta-analysis showed bleeding risk with apixaban in patients with mild renal impairment was significantly less (RR 0.80) compared with conventional anticoagulants 7

Critical Drug Interactions

• Avoid concomitant use of dual P-glycoprotein and strong CYP3A4 inhibitors or inducers, as these significantly alter apixaban levels 1, 5
• P-glycoprotein inhibitors may increase apixaban plasma concentrations, particularly problematic in patients with CKD 1
• Apixaban is a substrate of P-gp and breast cancer resistance protein 4

Important Caveats and Pitfalls

• Bleeding can occur at uncommon sites (pleura, pericardium, intracranial space) in severe kidney disease, even with guideline-based dosing 5, 8
• All anticoagulants carry increased bleeding risk in severe renal impairment 1, 5
• The European Heart Rhythm Association does not recommend routine NOAC use in CrCl <15 mL/min or dialysis due to limited hard endpoint data, though U.S. guidelines are more permissive 1, 5
• Edoxaban is absolutely contraindicated in ESRD or dialysis and should never be used 5
• Warfarin may cause calciphylaxis in ESRD patients, a painful and often lethal condition 1