What are the considerations for using Eliquis (apixaban) in patients with Chronic Kidney Disease (CKD) stage 4?

Using Apixaban in CKD Stage 4

Apixaban can be used with caution in CKD stage 4 patients (CrCl 15-29 mL/min) at a reduced dose of 2.5 mg twice daily, with evidence suggesting it may have a better safety profile than warfarin in this population. 1

Dosing Recommendations for Apixaban in CKD Stage 4

• For patients with CKD stage 4 (CrCl 15-29 mL/min), apixaban should be prescribed at a reduced dose of 2.5 mg twice daily 1, 2
• Dose reduction is also required if the patient has at least two of the following characteristics:
  • Age ≥80 years
  • Body weight ≤60 kg
  • Serum creatinine ≥1.5 mg/dL 2

Evidence Supporting Apixaban Use in CKD Stage 4

• The 2024 KDIGO guidelines recommend non-vitamin K antagonist oral anticoagulants (NOACs) over vitamin K antagonists (e.g., warfarin) for thromboprophylaxis in atrial fibrillation patients with CKD G1-G4 (1C recommendation) 1
• Apixaban has the lowest renal clearance (27%) among NOACs, making it potentially more suitable for patients with impaired renal function 1
• Meta-analyses of observational studies have shown that apixaban is associated with a lower risk of major bleeding compared to warfarin in advanced CKD patients, with no significant difference in thromboembolic events 3, 4
• A retrospective cohort study found similar major bleeding rates at 3 months between apixaban and warfarin in advanced CKD patients, but lower bleeding rates with apixaban between 6-12 months 5

Safety Considerations

• Regular monitoring of renal function is essential in CKD patients on NOACs, with more frequent evaluation recommended for those with CrCl <60 mL/min 1
• For patients with CrCl <60 mL/min, renal function should be evaluated at least every 6-12 months (calculated by dividing CrCl by 10 to obtain minimum frequency in months) 1
• Additional monitoring is warranted during acute illness (infections, heart failure exacerbations) that may transiently affect renal function 1
• Concomitant use of medications that may increase bleeding risk should be carefully evaluated 1

Comparative Safety Profile

• Apixaban has been associated with lower rates of major bleeding compared to warfarin in patients with advanced CKD 3, 6
• A meta-analysis of 43,850 patients from observational cohort studies found that apixaban was associated with reduced risk of major bleeding compared to warfarin (pooled OR 0.42; 95% CI 0.28-0.61) 3
• In dialysis patients specifically, the pooled OR for major bleeding was 0.27 (95% CI 0.07-0.95) favoring apixaban 3
• No significant differences in thromboembolic events have been observed between apixaban and warfarin in advanced CKD patients 3, 4

Important Caveats

• The FDA label notes that while apixaban can be used in ESRD patients on dialysis, "it is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as was seen in ARISTOTLE" 2
• Major clinical trials evaluating apixaban largely excluded patients with CrCl <25 mL/min 1, 7
• The European Medicines Agency has approved apixaban, rivaroxaban, and edoxaban (but not dabigatran) for use in patients with severe CKD (Stage 4, CrCl 15-29 mL/min) at reduced doses 1
• The NCCN guidelines list CrCl <30 mL/min as a contraindication for apixaban in cancer-associated venous thromboembolic disease, noting "insufficient data to support safe apixaban dosing in these patients" 1

Practical Approach

• Carefully assess stroke and bleeding risks using validated tools (CHA₂DS₂-VASc and HAS-BLED) 1
• Consider apixaban 2.5 mg twice daily for CKD stage 4 patients requiring anticoagulation 1
• Monitor renal function at least every 3 months in CKD stage 4 patients 1
• Reassess the need for continued anticoagulation periodically, weighing benefits against risks 1
• For patients transitioning to CKD stage 5 or dialysis, a careful reassessment of anticoagulation strategy is warranted 1