Apixaban Dosing in End-Stage Renal Disease
For patients with ESRD on hemodialysis, start with apixaban 5 mg twice daily, reducing to 2.5 mg twice daily only if the patient meets at least two of three additional criteria: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL. 1
FDA-Approved Dosing Algorithm
The FDA label explicitly states that for ESRD patients on intermittent hemodialysis, the standard dose of 5 mg twice daily produces apixaban concentrations and pharmacodynamic activity similar to those observed in the pivotal ARISTOTLE trial. 1 This recommendation is based on pharmacokinetic data showing that ESRD results in only a 36% increase in apixaban exposure with no increase in peak concentration, and hemodialysis itself has minimal impact on drug clearance (reducing exposure by only 14%). 2
The dose reduction criteria are cumulative—you need at least 2 of the 3 characteristics present to justify reducing to 2.5 mg twice daily: 1
- Age ≥80 years
- Body weight ≤60 kg
- Serum creatinine ≥1.5 mg/dL
Guideline Support and Clinical Evidence
The American Heart Association, American College of Cardiology, and Heart Rhythm Society guidelines support using either 5 mg or 2.5 mg twice daily in dialysis-dependent patients, with the 2019 focused update stating that apixaban use "might be reasonable" in this population. 3, 4 The American College of Cardiology specifically recommends apixaban 5 mg twice daily for stable hemodialysis patients, with dose reduction only when the additional criteria are met. 4
Apixaban is strongly preferred over other DOACs in ESRD because it has the lowest renal clearance at 27%, compared to dabigatran (80%), rivaroxaban (66%), and edoxaban (50%). 4, 5 In fact, dabigatran, rivaroxaban, and edoxaban are considered Class III (no benefit) in ESRD patients, and edoxaban is absolutely contraindicated in this population. 3, 4
Clinical Outcomes Data
Large observational studies provide compelling evidence for standard-dose apixaban in ESRD. A US Renal Data System analysis of 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 (2.5 mg twice daily) and warfarin, while maintaining lower major bleeding risk than warfarin. 4, 5
Meta-analyses consistently show apixaban reduces major bleeding risk by 42-58% compared to warfarin in ESRD patients, with no excess thromboembolic risk. 6, 7 The pooled odds ratio for major bleeding with apixaban versus warfarin is 0.42 (95% CI: 0.28-0.61) across all studies, and 0.27 (95% CI: 0.07-0.95) specifically in dialysis patients. 7
Critical Pharmacokinetic Rationale
The 2.5 mg twice daily dose in dialysis patients produces steady-state drug exposure comparable to 5 mg twice daily in patients with preserved renal function, which explains why this lower dose is appropriate when additional risk factors are present. 4, 5 However, the clinical outcomes data suggest that most ESRD patients benefit from the standard 5 mg dose unless they meet the additional reduction criteria. 4
Hemodialysis removes only approximately 14% of apixaban exposure, with a dialysis clearance of about 18 mL/min, making timing of administration relative to dialysis sessions clinically insignificant. 1, 2
Important Drug Interactions and Monitoring
Avoid concomitant use with combined P-glycoprotein and strong CYP3A4 inhibitors (ketoconazole, ritonavir, itraconazole) or inducers (rifampin, carbamazepine, phenytoin), as these significantly alter apixaban levels. 4, 5 If a strong dual inhibitor must be used with the 5 mg dose, reduce to 2.5 mg twice daily. 4
Do not combine apixaban with antiplatelet therapy in ESRD patients unless absolutely necessary (e.g., recent PCI), as this substantially elevates bleeding risk. 4, 5
Reassess renal function every 1-3 months in patients with declining kidney function, though the dose adjustment criteria for ESRD remain the same regardless of whether creatinine clearance is 10 mL/min or the patient is dialysis-dependent. 5
Warfarin as Alternative
Warfarin remains an alternative if well-managed with time in therapeutic range (TTR) >65-70%, but it carries increased bleeding risk and did not reduce deaths, ischemic events, or strokes in recent meta-analyses of dialysis patients. 4, 5 Additionally, warfarin may cause calciphylaxis, a rare but potentially lethal complication involving calcification and occlusion of cutaneous arteries. 4
Common Prescribing Errors to Avoid
The most frequent error is inappropriately reducing apixaban to 2.5 mg twice daily based on ESRD alone or a single dose-reduction criterion (such as age 75 years or creatinine 1.3 mg/dL). 8 ESRD by itself does NOT trigger dose reduction—you must have at least 2 of the 3 specified criteria. 1
Another pitfall is avoiding apixaban entirely in ESRD due to lack of randomized trial data, when substantial observational evidence and FDA approval support its use. 1, 9
Left Atrial Appendage Occlusion
For ESRD patients at exceptionally high risk of both stroke and bleeding who cannot tolerate any anticoagulation, consider percutaneous left atrial appendage closure (Watchman device) as an alternative to lifelong anticoagulation. 4