How should apixaban be dosed in patients with non‑valvular atrial fibrillation or venous thrombo‑embolism who have impaired renal function, considering age, body weight, serum creatinine, and creatinine clearance?

Apixaban Dosing in Renal Impairment

For patients with non-valvular atrial fibrillation, reduce apixaban to 2.5 mg twice daily only when at least TWO of the following three criteria are met: age ≥80 years, body weight ≤60 kg, OR serum creatinine ≥1.5 mg/dL—renal impairment alone does NOT trigger dose reduction unless it meets this threshold AND is combined with another criterion. 1, 2

Dose-Reduction Algorithm ("2-of-3 Rule")

• Standard dose: 5 mg twice daily for patients with 0 or 1 dose-reduction criteria, regardless of moderate renal impairment (CrCl 30-59 mL/min). 1, 3, 2

• Reduced dose: 2.5 mg twice daily only when ≥2 of these criteria are present:

  1. Age ≥80 years
  2. Body weight ≤60 kg
  3. Serum creatinine ≥1.5 mg/dL 1, 2

• Critical point: A single criterion—such as age 78 years, CrCl 44 mL/min, or weight 65 kg—does NOT justify dose reduction; you must count two or more criteria. 1, 4

Renal Function-Specific Dosing

Moderate Renal Impairment (CrCl 30-59 mL/min / CKD Stage 3)

• Use 5 mg twice daily unless the patient meets ≥2 dose-reduction criteria. 1, 2
• Apixaban has only 27% renal clearance, making it the safest DOAC in moderate CKD compared to dabigatran (80%) or rivaroxaban (66%). 1
• The ARISTOTLE trial demonstrated consistent efficacy and safety of 5 mg twice daily in patients with isolated moderate renal impairment. 1, 4

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

• Mandatory dose: 2.5 mg twice daily for ALL patients, regardless of age or weight. 1, 2
• This is the only scenario where renal function alone dictates dose reduction without requiring additional criteria. 1

End-Stage Renal Disease (CrCl <15 mL/min or Dialysis)

• FDA-approved regimen: 5 mg twice daily; reduce to 2.5 mg twice daily if age ≥80 years OR weight ≤60 kg (only ONE criterion required in dialysis, not two). 1, 2
• European guidelines contraindicate apixaban in dialysis, highlighting a regulatory discrepancy—U.S. practice permits use based on pharmacokinetic modeling. 1
• Apixaban is NOT recommended if CrCl <15 mL/min and the patient is NOT on dialysis. 2

Calculating Renal Function

• Always use the Cockcroft-Gault equation with actual body weight—this is what the FDA label and pivotal trials used. 1, 2
• Do NOT use eGFR for apixaban dosing; the two measures are not interchangeable and can lead to significant dosing errors. 1
• Reassess renal function at least annually, or every 3-6 months if CrCl <60 mL/min or clinical deterioration occurs. 1

Common Prescribing Errors & Pitfalls

• Underdosing is the most frequent error: 9.4-40.4% of apixaban prescriptions involve inappropriate dose reduction based on a single criterion (most commonly age ≥80 years alone or perceived bleeding risk). 1, 5

• Do NOT reduce the dose based on:

  • Isolated moderate CKD (CrCl 30-59 mL/min) 1
  • Age <80 years (e.g., a 78-year-old patient) 1
  • Perceived frailty or fall risk 1
  • History of bleeding without meeting formal criteria 1

• The 2-of-3 rule applies ONLY to atrial fibrillation dosing—it does NOT apply to VTE treatment, which uses 10 mg twice daily × 7 days, then 5 mg twice daily maintenance. 1, 6

Drug Interactions Requiring Dose Adjustment

• Reduce to 2.5 mg twice daily when using combined P-glycoprotein AND strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, itraconazole) in patients otherwise receiving 5 mg twice daily. 1, 2
• Avoid apixaban entirely with strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin). 1, 2

Evidence Supporting Standard Dosing in Moderate CKD

• The ARISTOTLE trial enrolled patients with isolated moderate renal impairment receiving 5 mg twice daily and demonstrated similar efficacy (HR 0.94 for stroke) and safety (HR 0.68 for major bleeding) compared to warfarin. 4
• Patients with one dose-reduction criterion had higher baseline risk but showed consistent benefit from 5 mg twice daily versus warfarin, with no interaction between dose-reduction criteria and treatment effect (P=0.36 for efficacy, P=0.71 for bleeding). 4
• Post-hoc analyses show apixaban may reduce loss of GFR compared to warfarin, suggesting a possible renoprotective effect. 1

Comparative Safety in Advanced CKD

• A meta-analysis of >78,000 patients with non-dialysis CKD showed apixaban reduced major bleeding by 35% (HR 0.69) and stroke/systemic embolism by 25% compared to warfarin. 1
• Warfarin-related nephropathy occurs twice as frequently in CKD patients and promotes vascular calcification by inhibiting Matrix Gla Protein. 1

Practical Implementation Steps

1. Calculate CrCl using Cockcroft-Gault with actual body weight. 1
2. Count dose-reduction criteria (age, weight, serum creatinine). 1, 2
3. Apply dosing algorithm:
   • CrCl >30 mL/min: 5 mg BID (unless ≥2 criteria → 2.5 mg BID)
   • CrCl 15-29 mL/min: 2.5 mg BID for all patients
   • CrCl <15 mL/min on dialysis: 5 mg BID (reduce to 2.5 mg if age ≥80 OR weight ≤60 kg) 1, 2
4. Screen for drug interactions and adjust accordingly. 1, 2
5. Monitor renal function annually (or every 3-6 months if CrCl <60 mL/min). 1