Is apixaban (eliquis) validated for use in patients with end-stage renal disease (ESRD)?

Apixaban Use in End-Stage Renal Disease

Apixaban is FDA-approved and can be used in patients with end-stage renal disease on hemodialysis at a dose of 5 mg twice daily (or 2.5 mg twice daily if age ≥80 years or weight ≤60 kg), though this approval is based on pharmacokinetic data rather than randomized controlled trials. 1

Regulatory Status and Evidence Base

• The FDA explicitly approves apixaban for use in ESRD patients on dialysis, making it the only direct oral anticoagulant with this indication 1, 2
• However, clinical efficacy and safety studies with apixaban did not enroll patients with ESRD on dialysis, so dosing recommendations are based on pharmacokinetic and pharmacodynamic data rather than hard clinical endpoints 1
• The approval relies on pharmacokinetic studies showing that apixaban 5 mg twice daily in dialysis patients produces drug concentrations and anti-factor Xa activity similar to those observed in the pivotal ARISTOTLE trial 1, 3

Dosing Algorithm for ESRD on Hemodialysis

Start with 5 mg twice daily as the standard dose, then reduce to 2.5 mg twice daily ONLY if the patient meets at least one of these criteria: 4, 5

• Age ≥80 years, OR
• Body weight ≤60 kg

Critical caveat: The standard 5 mg twice daily dose produces supratherapeutic drug levels in dialysis patients, but observational data suggests this may actually be beneficial 4, 5

Comparative Safety and Efficacy Evidence

• A meta-analysis of 43,850 patients showed apixaban was associated with 58% lower risk of major bleeding compared to warfarin (pooled OR 0.42,95% CI 0.28-0.61) 2
• In ESRD patients specifically on dialysis, the risk reduction for major bleeding was even greater (pooled OR 0.27,95% CI 0.07-0.95) 2
• Large observational data from 25,523 dialysis patients demonstrated that standard-dose apixaban (5 mg twice daily) was associated with lower risk of stroke/embolism and death compared to both reduced-dose apixaban and warfarin 5
• For acute VTE treatment in ESRD, apixaban showed lower risk of major bleeding (HR 0.81), intracranial bleeding (HR 0.69), and gastrointestinal bleeding (HR 0.82) compared to warfarin 6

Pharmacokinetic Rationale

• Apixaban has the lowest renal clearance (27%) among all direct oral anticoagulants, making it theoretically the most suitable for severe renal impairment 7, 4
• A single 5 mg dose in ESRD patients resulted in only 36% higher AUC and 10% lower Cmax compared to patients with normal renal function 3
• Hemodialysis removes only 14% of apixaban, indicating minimal dialytic clearance 3
• The 2.5 mg twice daily dose in dialysis patients produces drug exposure comparable to 5 mg twice daily in patients with preserved renal function 4, 5

Guideline Recommendations

The 2018 CHEST guidelines provide the most conservative approach: 7

• For ESRD (CrCl <15 mL/min or dialysis-dependent), individualized decision-making is appropriate (ungraded consensus-based statement) 7
• NOACs should generally not be used, although in the USA, apixaban 5 mg twice daily is approved for use in AF patients receiving hemodialysis 7
• Well-managed warfarin with TTR >65-70% is suggested as an alternative 7

The 2019 AHA/ACC/HRS guidelines are more permissive: 5

• Use of warfarin or apixaban might be reasonable in dialysis-dependent patients with atrial fibrillation (Class IIb recommendation) 5

Critical Pitfalls and Caveats

Avoid these common errors:

• Do not use edoxaban in ESRD - it is absolutely contraindicated due to 50% renal excretion 5
• Avoid rivaroxaban and dabigatran - both show 45-76% increased major bleeding risk compared to warfarin in dialysis patients 5
• Do not combine with antiplatelet therapy - concomitant aspirin substantially elevates bleeding risk in ESRD patients 7, 4
• Avoid dual P-glycoprotein and strong CYP3A4 inhibitors/inducers - these significantly alter apixaban levels 4, 1

Monitoring Considerations

• INR monitoring is not recommended for apixaban, though rare cases of extreme INR elevation (>20) have been reported in ESRD patients 8
• Renal function should be reassessed every 1-3 months in patients with declining kidney function 4
• Use Cockcroft-Gault equation for creatinine clearance calculations, as this was used in pivotal trials 4

Alternative to Anticoagulation

• Left atrial appendage occlusion (Watchman device) should be considered as an alternative for patients at high risk of both stroke and bleeding who cannot tolerate anticoagulation 5

Bottom Line for Clinical Practice

Despite the lack of randomized trial data, apixaban 5 mg twice daily (or 2.5 mg twice daily if elderly or low weight) is the preferred anticoagulant in ESRD patients on hemodialysis based on FDA approval, favorable pharmacokinetics, and superior safety profile compared to warfarin in large observational studies. 5, 1, 2, 6