What is the appropriate dosing of apixaban (apixaban) for a patient with chronic kidney disease (CKD) on hemodialysis (HD) requiring prevention of thromboembolic events?

Apixaban for Thromboprophylaxis in CKD Patients on Hemodialysis

Primary Recommendation

For patients with end-stage renal disease on hemodialysis requiring anticoagulation, apixaban 5 mg twice daily is the FDA-approved dose, though emerging evidence strongly suggests 2.5 mg twice daily produces more appropriate drug levels and may be safer. 1

Dosing Algorithm for HD Patients

Standard Approach (FDA-Approved)

• Apixaban 5 mg twice daily is the FDA-approved dose for ESRD patients on stable hemodialysis 1
• This approval is based on pharmacokinetic data showing similar concentrations to non-ESRD patients in the ARISTOTLE trial 1

Evidence-Based Alternative (Increasingly Preferred)

• Apixaban 2.5 mg twice daily produces steady-state drug exposure in dialysis patients comparable to 5 mg twice daily in patients with normal renal function 2, 3
• Pharmacokinetic studies demonstrate that 5 mg twice daily results in supratherapeutic levels in dialysis patients 2, 3
• The American College of Cardiology recommends dose reduction to 2.5 mg twice daily if patient is ≥80 years old OR weighs ≤60 kg 2

Clinical Outcomes Data

• Large observational study (n=25,523) from US Renal Data System showed standard-dose apixaban (5 mg BID) associated with lower risk of stroke/embolism and death compared to reduced-dose (2.5 mg BID) and warfarin 2
• However, this conflicts with pharmacokinetic data showing supratherapeutic levels at 5 mg BID 2, 3
• Meta-analyses demonstrate apixaban associated with lower major bleeding risk compared to warfarin with no excess thromboembolic events 2

Guideline Recommendations by Society

American Heart Association/ACC/HRS (Most Recent)

• States that apixaban 5 mg OR 2.5 mg twice daily might be reasonable in dialysis-dependent patients 2
• Acknowledges limited evidence base with soft recommendation 2

American College of Chest Physicians (2018)

• Suggests individualized decision-making for ESRD patients 4
• States NOACs should generally not be used, but notes apixaban 5 mg BID is approved in US for AF patients on hemodialysis 4, 2
• Recommends well-managed warfarin (TTR >65-70%) as alternative 4

European Heart Rhythm Association

• Does not recommend routine NOAC use in patients with CrCl <15 mL/min or on dialysis due to limited hard endpoint data 2

Safety Considerations

Bleeding Risk

• Major bleeding rates in dialysis patients on apixaban range from 7-14% in observational studies 5
• One retrospective study (n=66) showed major bleeding in 15.2% and minor bleeding in 36.4% of ESRD patients on apixaban 6
• BMI was identified as main independent risk factor for bleeding (OR=0.9,95% CI: 0.8-0.99) 6
• Apixaban demonstrates lower intracranial hemorrhage risk compared to warfarin 2

Drug Interactions

• Avoid concomitant use of dual P-glycoprotein AND strong CYP3A4 inhibitors/inducers as these significantly alter apixaban levels 2, 3
• Avoid concomitant antiplatelet therapy as it substantially elevates bleeding risk 4, 2

Pharmacokinetic Rationale

• Apixaban has lowest renal clearance (27%) among all DOACs, making it theoretically most suitable for severe renal impairment 2, 3
• Despite low renal clearance, drug accumulation still occurs in ESRD 5

Practical Clinical Approach

When to Use Apixaban vs Warfarin

• Consider apixaban as reasonable alternative to warfarin in dialysis patients requiring anticoagulation for AF or VTE 2
• Apixaban preferable to other NOACs due to lowest renal clearance 2
• Warfarin remains alternative if well-managed (TTR >65-70%), though carries increased bleeding risk 4, 2
• Warfarin did not reduce deaths, ischemic events, or strokes in recent meta-analyses of dialysis patients 2

Monitoring

• No routine laboratory monitoring required for apixaban (unlike warfarin) 2
• Monitor clinically for signs of bleeding throughout therapy 7
• Anti-factor Xa levels can be measured but correlation with clinical outcomes uncertain 8

Alternative Strategy

• Left atrial appendage occlusion should be considered in dialysis patients at high risk of both stroke and bleeding, avoiding anticoagulation-related bleeding risks entirely 2

Critical Pitfalls to Avoid

• Do not assume standard dosing is universally safe in ESRD—verify patient meets criteria and consider pharmacokinetic data favoring lower dose 5
• Do not use edoxaban—it is absolutely contraindicated in ESRD/dialysis due to 50% renal excretion 2
• Do not use apixaban with mechanical heart valves—this is an absolute contraindication 2
• Do not combine with antiplatelet therapy unless absolutely necessary—this dramatically increases bleeding risk 4, 2

Unresolved Controversy

The major clinical dilemma is the discordance between pharmacokinetic data (favoring 2.5 mg BID) and observational outcomes data (favoring 5 mg BID) 2, 3. Until prospective randomized trials are completed, clinicians must weigh:

• 5 mg BID: FDA-approved, better outcomes in observational data, but supratherapeutic levels 2, 1
• 2.5 mg BID: More appropriate drug levels, but inferior outcomes in observational studies (possibly due to confounding by indication) 2, 3

A reasonable approach is to start with 5 mg BID per FDA approval, but reduce to 2.5 mg BID if patient is ≥80 years, weighs ≤60 kg, or experiences bleeding complications. 2