Anticoagulant Selection in Atrial Fibrillation with Advanced Chronic Kidney Disease: Clinical Practice Recommendations

Introduction

Patients with atrial fibrillation (AF) and severe chronic kidney disease (CKD) face an increased risk of both bleeding and thromboembolism. Selecting an anticoagulant for patients with CKD is critical yet challenging due to limited data on the safety of these drugs in this population. Recently published observational studies suggest that among direct oral anticoagulants (DOACs), apixaban is a safer choice compared to alternatives such as rivaroxaban or warfarin, due to its lower risk of bleeding.

Overview of Available Oral Anticoagulants

Apixaban: The Preferred ChoiceApixaban is often preferred for patients with AF and severe CKD, including those on dialysis. Compared to other DOACs, apixaban relies less on renal clearance, making it safer for patients with impaired kidney function. Observational studies suggest that apixaban is associated with a lower risk of major bleeding compared to warfarin and rivaroxaban, with similar efficacy in preventing stroke and systemic embolism.

The standard dose is 5 mg twice daily, but in patients with two or more of the following criteria—age ≥80 years, body weight ≤60 kg, or serum creatinine ≥133 µmol/L—the dose is adjusted to 2.5 mg twice daily. However, data on safety in patients with creatinine clearance (CrCl) <15 mL/min and those on dialysis remain insufficient.

RivaroxabanRivaroxaban is an alternative for patients with AF and CKD with a CrCl of 15–50 mL/min. The recommended dose for patients with CrCl >50 mL/min is 20 mg once daily with the largest meal of the day. For patients with CrCl 15–50 mL/min, the recommended dose is 15 mg once daily with the largest meal. However, in patients with CrCl <15 mL/min or on dialysis, rivaroxaban should generally be avoided due to the higher risk of bleeding.

DabigatranThe use of dabigatran in CKD is limited due to its significant renal elimination (80–85%). It is recommended for patients with CrCl >30 mL/min at a dose of 150 mg twice daily. In those with CrCl between 15–30 mL/min, the dose is reduced to 75 mg twice daily, but its use is discouraged in this group due to insufficient safety data. Dabigatran is contraindicated in patients with CrCl <15 mL/min or on dialysis.

EdoxabanEdoxaban can be used in patients with CKD and CrCl 15–50 mL/min, with dosing adjustments according to the degree of renal impairment. In patients with CrCl >95 mL/min, its efficacy is reduced due to high renal clearance. For patients with CrCl >50–95 mL/min, the recommended dose is 60 mg once daily. In patients with severe CKD (CrCl 15–30 mL/min), a reduced dose of 30 mg once daily is recommended. Data on use in patients with CrCl <15 mL/min are lacking, and it is not recommended.

Warfarin as an Alternative in Advanced CKDIn patients with severe CKD, especially those on dialysis, warfarin remains an alternative to DOACs. It allows therapeutic monitoring and dose adjustment, which is beneficial in cases of acute worsening of renal function. The target INR is 2.0–3.0, and maintaining >70% time in therapeutic range is considered optimal. However, variability in effect and numerous drug and food interactions remain major challenges with warfarin therapy.

Why Is Apixaban the DOAC of Choice in CKD?

Its lower dependence on renal clearance (approximately 25%) makes it less affected by impaired kidney function compared to other DOACs. Studies consistently show that apixaban carries a lower risk of major bleeding compared to warfarin and rivaroxaban in patients with severe CKD, with similar efficacy in stroke prevention. In patients with AF and severe CKD not requiring dialysis, apixaban has demonstrated a more favorable safety profile, supporting its role as the first-choice anticoagulant in this population.

Evidence Supporting Apixaban in CKD Patients

1. ARISTOTLE study: A subgroup analysis of 269 patients with AF and CrCl 25–30 mL/min demonstrated a significantly lower risk of major bleeding with apixaban compared to warfarin (HR 0.34).

2. Observational studies: An observational study of 6,794 adults with severe CKD not on dialysis found that apixaban was associated with a lower risk of major bleeding compared to warfarin (1.5 vs. 2.9 per 100 person-years) and rivaroxaban, while rates of stroke/systemic embolism and mortality were similar. Rivaroxaban was associated with a higher risk of major bleeding (4.9 vs. 2.9 per 100 person-years) without differences in stroke/systemic embolism or death. Compared with rivaroxaban, apixaban was associated with a reduced risk of major bleeding (HR 0.53 [95% CI, 0.36–0.78]).

DOACs and Renal Function

Renal elimination rates for each DOAC are a key factor in determining suitability:

• Dabigatran: 80–85%

• Edoxaban: 35%

• Rivaroxaban: 35%

• Apixaban: 25%

Because of their reliance on renal clearance, DOACs must be prescribed with caution in CKD patients. In severe CKD (CrCl <30 mL/min), warfarin or adjusted doses of low-molecular-weight heparin are often preferred over DOACs. However, new evidence supports the safe and effective use of apixaban even in patients with significant renal impairment.

DOAC Selection by Kidney Function

1. Mild to moderate CKD (CrCl 30–50 mL/min): All DOACs are generally safe with appropriate dose adjustments.

2. Severe CKD (CrCl <30 mL/min) or dialysis: Apixaban is the preferred option based on observational data. Warfarin remains an alternative due to better monitoring options.

3. Advanced CKD (CrCl <15 mL/min): Data on DOACs are insufficient. Warfarin or adjusted low-molecular-weight heparin are recommended as first-line therapy.

Conclusion

Selecting an anticoagulant for patients with AF and severe CKD requires careful consideration of the balance between bleeding risk and thromboembolism prevention. Among available DOACs, apixaban stands out for its favorable safety profile and lower dependence on renal clearance. However, for patients with CrCl <15 mL/min or those on dialysis, warfarin remains the recommended alternative. Clinicians must consider patient-specific factors, including age, weight, bleeding risk, and renal function, when choosing an anticoagulant therapy.

Note: Clinicians must also remain mindful of significant pharmacokinetic interactions between DOACs and other drugs, as the risk of clinically important interactions is higher in CKD patients.

For more on safe prescribing of DOACs, see our previous blog posts:

• Anticoagulant Therapy in Patients with Impaired Renal Function

• Anticoagulant Therapy in Elderly Patients with Atrial Fibrillation

References:

1. Xu Y, Ballew SH, Chang AR, Inker LA, Grams ME, Shin JI. Risk of Major Bleeding, Stroke/Systemic Embolism, and Death Associated With Different Oral Anticoagulants in Patients With Atrial Fibrillation and Severe Chronic Kidney Disease. J Am Heart Assoc. 2024 Aug 20;13(16):e034641. doi: 10.1161/JAHA.123.034641.

2. Stanifer JW, Pokorney SD, Chertow GM, Hohnloser SH, Wojdyla DM, Garonzik S, Byon W, Hijazi Z, Lopes RD, Alexander JH, Wallentin L, Granger CB. Apixaban Versus Warfarin in Patients With Atrial Fibrillation and Advanced Chronic Kidney Disease. Circulation. 2020 Apr 28;141(17):1384-1392. doi: 10.1161/CIRCULATIONAHA.119.044059.

3. Sažetci opisa svojstava lijeka za DOAK-e. Dostupno na: HALMED. Baza lijekova: https://www.halmed.hr/lijekovi/baza-lijekova/