Apixaban Dosing in Kidney Dysfunction
For patients with moderate renal impairment (CrCl 30-50 mL/min), use apixaban 5 mg twice daily unless the patient meets at least 2 of 3 dose-reduction criteria (age ≥80 years, weight ≤60 kg, or serum creatinine ≥1.5 mg/dL), in which case reduce to 2.5 mg twice daily. 1, 2, 3
Dosing Algorithm by Renal Function
Normal to Mild Impairment (CrCl >50 mL/min)
- Standard dose: 5 mg twice daily 1, 2
- Reduce to 2.5 mg twice daily only if patient meets ≥2 of the following criteria: 1, 2, 3
- Age ≥80 years
- Body weight ≤60 kg
- Serum creatinine ≥1.5 mg/dL
- No dose adjustment needed based on renal function alone in this range 2, 3
Moderate Impairment (CrCl 30-50 mL/min)
- Standard dose: 5 mg twice daily 1, 2
- Apply the same 3-criteria rule: reduce to 2.5 mg twice daily only if ≥2 criteria are met 1, 2, 3
- Apixaban is preferred over other DOACs in this range due to its low renal clearance (27%) 2, 4, 5
- Critical pitfall: The most common prescribing error is reducing the dose based on a single criterion (such as renal function alone) rather than requiring two criteria 6
Severe Impairment (CrCl 15-29 mL/min)
- Recommended dose: 2.5 mg twice daily 1, 2
- The 2019 AHA/ACC/HRS guidelines support either 5 mg or 2.5 mg twice daily, but most recent evidence favors 2.5 mg twice daily 1, 2
- European guidelines explicitly approve apixaban with dose reduction for severe CKD 2
- Apixaban has the lowest renal clearance among all DOACs, making it the preferred agent in severe renal impairment 2, 4
End-Stage Renal Disease on Dialysis (CrCl <15 mL/min)
- FDA-approved dose: 5 mg twice daily, reduced to 2.5 mg twice daily if age ≥80 years OR weight ≤60 kg 4, 3
- However, pharmacokinetic data strongly support 2.5 mg twice daily as the preferred dose, as this produces drug exposure comparable to 5 mg twice daily in patients with normal renal function 2, 4
- Observational data from 25,523 dialysis patients showed standard-dose apixaban (5 mg twice daily) was associated with lower stroke/embolism and death compared to reduced-dose, but this conflicts with pharmacokinetic evidence showing supratherapeutic levels at 5 mg twice daily 2, 4
- The safest approach based on pharmacokinetics is 2.5 mg twice daily 2, 4
Key Pharmacokinetic Considerations
- Apixaban has only 27% renal clearance, the lowest among all DOACs (compared to dabigatran 80%, rivaroxaban 35%, edoxaban 50%) 1, 2, 4
- In severe renal impairment, apixaban AUC increases by 44% compared to normal renal function 5
- Apixaban is minimally dialyzable (14%), so timing relative to dialysis is less critical than with dabigatran 1
Monitoring Requirements
- Calculate creatinine clearance using the Cockcroft-Gault equation, not eGFR, as this is what was used in clinical trials 1, 2, 6
- Reassess renal function at least annually, and every 3-6 months if CrCl <60 mL/min or declining 2, 6
- No routine INR monitoring is required or recommended for apixaban 6
Critical Drug Interactions
- Avoid concomitant use of dual P-glycoprotein and strong CYP3A4 inhibitors or inducers, particularly in patients with CKD, as these significantly alter apixaban levels 1, 2, 4
- Common interacting drugs include ketoconazole, ritonavir, rifampin, and carbamazepine 1, 2
- Avoid concomitant antiplatelet therapy as it substantially elevates bleeding risk 4
Bleeding Risk Considerations
- All anticoagulants carry increased bleeding risk in severe renal impairment 2, 4
- Bleeding can occur at uncommon sites (pleura, pericardium, intracranial space) in severe kidney disease, even with guideline-based dosing 7
- Apixaban has lower major bleeding risk compared to warfarin in dialysis patients 4
- Apixaban has lower intracranial hemorrhage risk compared to warfarin 4
Comparison to Warfarin in Advanced CKD
- In dialysis patients, apixaban is associated with lower major bleeding risk than warfarin 4
- Warfarin carries risk of calciphylaxis in ESRD, a painful and often lethal condition 2, 4
- Meta-analyses show warfarin did not reduce deaths, ischemic events, or strokes in dialysis patients but increased major bleeding 4