What are the implications of using Apixaban (apixaban) in patients with Hemodialysis (HD)?

From the Guidelines

Apixaban can be used in hemodialysis (HD) patients, and according to the latest evidence, standard-dose apixaban is associated with a lower risk of stroke, major bleeding, and mortality when compared with warfarin in patients on hemodialysis. When considering the use of apixaban in HD patients, several factors should be taken into account, including the patient's individual bleeding risk, comorbidities, and potential drug interactions, particularly with strong dual inhibitors of CYP3A4 and P-glycoprotein 1. Some key points to consider when using apixaban in HD patients include:

• Apixaban is minimally removed by hemodialysis (approximately 7-14%) due to its high protein binding, so no supplemental dosing is needed after dialysis sessions 1.
• For HD patients with atrial fibrillation, apixaban is often preferred over warfarin due to lower bleeding risk while maintaining efficacy for stroke prevention 1.
• When transitioning from warfarin to apixaban, discontinue warfarin and start apixaban when INR is below 2.0 1.
• For procedures, apixaban should typically be held for 24-48 hours before interventions with moderate-high bleeding risk, with longer intervals for patients with impaired renal function 1. It is essential to note that two RCTs, RENAL-AF and AXADIA, are underway to examine the safety and efficacy of NOACs compared with warfarin in the population on dialysis, and their results may provide further guidance on the use of apixaban in HD patients 1. However, based on the current evidence, standard-dose apixaban is a viable option for HD patients, offering a more predictable anticoagulant effect and lower bleeding risk compared to warfarin. In terms of dosing, apixaban can be used at a standard dose of 5 mg twice daily for most indications, with dose reduction to 2.5 mg twice daily if the patient meets two of three criteria: age ≥80 years, weight ≤60 kg, or serum creatinine ≥1.5 mg/dL 1. Ultimately, the decision to use apixaban in HD patients should be made on a case-by-case basis, taking into account the individual patient's characteristics and medical history.

From the FDA Drug Label

Patients with End-Stage Renal Disease on Dialysis Clinical efficacy and safety studies with apixaban did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, administration of apixaban at the usually recommended dose [see Dosage and Administration (2. 1)] will result in concentrations of apixaban and pharmacodynamic activity similar to those observed in the ARISTOTLE study [see Clinical Pharmacology (12. 3)]. 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 Hemodialysis in ESRD subjects: Systemic exposure to apixaban administered as a single 5 mg dose in ESRD subjects dosed immediately after the completion of a 4-hour hemodialysis session (post-dialysis) is 36% higher when compared to subjects with normal renal function

The use of apixaban in patients with Hemodialysis (HD) may result in higher systemic exposure, with a 36% increase in systemic exposure when administered after a 4-hour hemodialysis session. However, it is not known whether this will lead to similar stroke reduction and bleeding risk as seen in patients without ESRD on dialysis.

• Dose adjustment may be necessary for patients with nonvalvular atrial fibrillation who have at least two of the following characteristics:
  • age greater than or equal to 80 years
  • body weight less than or equal to 60 kg
  • serum creatinine greater than or equal to 1.5 mg/dL
• No dose adjustment is recommended for patients with renal impairment, including those with ESRD on dialysis, for other indications. 2

From the Research

Implications of Apixaban in Hemodialysis Patients

The use of apixaban in patients with end-stage renal disease (ESRD) on hemodialysis has been studied in several research papers 3, 4, 5, 6, 7. The implications of using apixaban in these patients can be summarized as follows:

• Bleeding Risk: The risk of bleeding is significant in patients with ESRD on hemodialysis treated with apixaban, with major bleeding events occurring in 15.2% of cases and minor bleeding events occurring in 36.4% of cases 3. BMI was found to be the main independent risk factor for bleeding in this population [OR = 0.9,95% CI: 0.8-0.99; p = 0.023] 3.
• Efficacy and Safety: Apixaban was associated with lower rates of major bleeding, gastrointestinal bleeding, intracranial bleeding, and stroke/systemic embolism compared to warfarin in patients with ESRD on hemodialysis 5. Apixaban had an overall favorable risk-benefit profile, with significant reductions in ischemic stroke, major bleeding, and intracranial bleeding compared to warfarin in ESRD patients on hemodialysis with non-valvular AF and/or venous thromboembolism 5.
• Pharmacokinetics and Pharmacodynamics: ESRD resulted in a modest increase (36%) in apixaban AUC and no increase in Cmax, and hemodialysis had a limited impact on apixaban clearance 6. A single 5-mg oral dose of apixaban was well tolerated in both healthy subjects and subjects with ESRD 6.
• Comparison to Warfarin: Apixaban may be a cautious consideration in hemodialysis patients until there is further insight into the effect of subsequent, multiple doses on drug accumulation and clinical outcomes 7. There were no observed differences in bleeding rates in patients receiving apixaban compared to those receiving warfarin 7.

Key Findings

• Apixaban is associated with a significant risk of bleeding in patients with ESRD on hemodialysis.
• BMI is the main independent risk factor for bleeding in this population.
• Apixaban has a favorable risk-benefit profile compared to warfarin in patients with ESRD on hemodialysis.
• ESRD results in a modest increase in apixaban AUC and no increase in Cmax, and hemodialysis has a limited impact on apixaban clearance.
• Apixaban may be a cautious consideration in hemodialysis patients until further insight into its effects is gained.

Considerations for Use

• Patients with ESRD on hemodialysis should be closely monitored for bleeding events when treated with apixaban.
• The dose of apixaban should be carefully considered in patients with ESRD on hemodialysis, taking into account the potential for drug accumulation and increased bleeding risk.
• Further studies are needed to fully understand the safety and efficacy of apixaban in patients with ESRD on hemodialysis.