What is the appropriate apixaban (Eliquis) dosing for a patient with end‑stage renal disease on intermittent hemodialysis, and when should the dose be reduced?

Apixaban Dosing in End-Stage Renal Disease on Hemodialysis

For patients with ESRD on intermittent hemodialysis, prescribe apixaban 5 mg twice daily, reducing to 2.5 mg twice daily only if the patient is ≥80 years old OR weighs ≤60 kg (only one criterion required for dialysis patients). 1, 2

FDA-Approved Dosing for Dialysis Patients

• The FDA prescribing information recommends apixaban 5 mg twice daily for patients with ESRD on hemodialysis, with dose reduction to 2.5 mg twice daily if the patient meets either age ≥80 years or body weight ≤60 kg. 2

• This dosing differs from non-dialysis patients, where two of three criteria (age ≥80 years, weight ≤60 kg, serum creatinine ≥1.5 mg/dL) are required for dose reduction. 3, 1

• The FDA approval is based on pharmacokinetic modeling showing that the standard 5 mg twice-daily dose in dialysis patients produces drug concentrations similar to those observed in the ARISTOTLE trial. 2

Pharmacokinetic Rationale

• Apixaban has only 27% renal clearance, making it the DOAC with the lowest renal dependence compared with dabigatran (≈80%) and rivaroxaban (≈66%). 1, 4

• A single-dose pharmacokinetic study showed that ESRD resulted in a modest 36% increase in apixaban AUC with no increase in peak concentration, and hemodialysis removed only 4% of the drug. 5, 6

• However, steady-state pharmacokinetic data reveal significant drug accumulation: apixaban 2.5 mg twice daily in dialysis patients produces drug exposure comparable to 5 mg twice daily in patients with normal renal function, while 5 mg twice daily leads to supratherapeutic levels (AUC 6045 ng·h/mL, above the 90th percentile). 6

Clinical Evidence Supporting Standard Dosing

• A large US Renal Data System observational study of 25,523 dialysis patients showed that standard-dose apixaban (5 mg twice daily) was associated with lower rates of stroke/embolism and death compared with both reduced-dose apixaban (2.5 mg twice daily) and warfarin. 1, 4

• The same cohort demonstrated a 28% reduction in major bleeding with apixaban versus warfarin (HR 0.72; 95% CI 0.59–0.87). 1, 4

• Despite pharmacokinetic concerns about supratherapeutic levels with 5 mg twice daily, real-world observational data consistently show superior clinical outcomes with the standard dose. 1, 4

Critical Dosing Pitfall to Avoid

• Do not empirically reduce apixaban to 2.5 mg twice daily based solely on perceived bleeding risk, frailty, or the presence of ESRD. Underdosing occurs in 10–40% of prescriptions and is associated with inferior stroke prevention and higher mortality. 1, 7

• The 2.5 mg twice-daily dose should be reserved only for dialysis patients who are ≥80 years old or weigh ≤60 kg, as specified by FDA labeling. 2, 1

Guideline Recommendations

• The 2019 AHA/ACC/HRS focused update states that apixaban use "might be reasonable" in dialysis-dependent patients with atrial fibrillation (Class IIb, moderate-quality evidence). 1, 4

• The 2020 ACC expert consensus recommends apixaban as a reasonable alternative to warfarin for ESRD patients on stable hemodialysis, with dose reduction only when age ≥80 years or weight ≤60 kg. 3, 1

Contraindicated Agents in Dialysis

• Dabigatran is absolutely contraindicated in dialysis patients due to 80% renal clearance and a 45–76% increased major bleeding risk. 4

• Rivaroxaban is not recommended due to 66% renal clearance and similarly elevated bleeding risk. 4

• Edoxaban is contraindicated due to 50% renal excretion and lack of dosing guidance for dialysis patients. 4

Monitoring Requirements

• No routine INR monitoring is required for apixaban, although rare cases of markedly elevated INR (>20) have been reported in dialysis patients. 8

• Renal function should be reassessed at least annually, though this is less relevant for established dialysis patients. 1

• Monitor for bleeding symptoms, particularly gastrointestinal bleeding, which remains the most common adverse event. 9, 10

Drug Interactions Requiring Dose Adjustment

• When apixaban is co-administered with both a strong P-glycoprotein inhibitor and a strong CYP3A4 inhibitor (e.g., ketoconazole, ritonavir, itraconazole), reduce the dose to 2.5 mg twice daily. 1, 4

• Avoid apixaban entirely with strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin), as they significantly reduce apixaban levels. 1, 4

Alternative Anticoagulation

• Warfarin remains an alternative but is associated with higher major bleeding risk, accelerated vascular calcification, and risk of calciphylaxis in dialysis patients. 4, 9

• If warfarin is used, target INR 2.0–3.0 with time-in-therapeutic range >65–70%. 4

• Left atrial appendage occlusion is a reasonable non-pharmacologic alternative for patients at high risk of both stroke and bleeding. 4

Regulatory Discrepancy

• The European Medicines Agency contraindicates all DOACs, including apixaban, in dialysis patients, reflecting a notable divergence from U.S. FDA approval. 4