What are the considerations for using oral anticoagulants in patients with Chronic Kidney Disease (CKD)?

From the Guidelines

Oral anticoagulants in chronic kidney disease (CKD) should be carefully selected, with direct oral anticoagulants (DOACs) generally preferred over warfarin in patients with mild to moderate CKD (stages 1-3), while warfarin remains the standard for severe CKD (stages 4-5) and dialysis patients, as supported by the most recent guidelines 1.

Key Considerations

• For patients with CKD requiring anticoagulation, the selection of anticoagulant therapy should be based on the risk of thromboembolism, irrespective of whether the AF pattern is paroxysmal, persistent, or permanent, as recommended by the 2019 AHA/ACC/HRS guideline 1.
• Renal function and hepatic function should be evaluated before initiation of a NOAC and should be reevaluated at least annually, with more frequent evaluation recommended if renal function is impaired, as suggested by the 2018 European Heart Rhythm Association practical guide 1.
• Among DOACs, apixaban (2.5-5mg twice daily) and rivaroxaban (15-20mg daily with food) can be used with dose reductions in moderate CKD, while dabigatran (75-150mg twice daily) requires significant dose reduction in moderate CKD and should be avoided in severe CKD, as indicated by the 2018 European Heart Rhythm Association practical guide 1.
• Edoxaban (30-60mg daily) also requires dose adjustment based on creatinine clearance, and its use is recommended with caution in patients with high creatinine clearance, as warned by the FDA and advised by the EMA, as mentioned in the 2018 European Heart Rhythm Association practical guide 1.

Monitoring and Dose Adjustments

• Regular monitoring of kidney function is essential as CKD can progress, necessitating dose adjustments, as emphasized by the 2018 European Heart Rhythm Association practical guide 1.
• The CKD-EPI equation estimating the glomerular filtration rate is recommended by the National Kidney Foundation, but in the context of NOAC treatment, renal function should preferably be estimated by calculating the CrCl using the Cockcroft–Gault method, as suggested by the 2018 European Heart Rhythm Association practical guide 1.

Patient-Specific Considerations

• For patients on dialysis, warfarin with an INR target of 2-3 remains the safest option, though apixaban 2.5mg twice daily may be considered in select cases, as recommended by the 2019 AHA/ACC/HRS guideline 1 and the 2018 European Heart Rhythm Association practical guide 1.
• The use of oral anticoagulants in patients with CKD and AF requires careful consideration of the individual patient's thromboembolic and bleeding risk, as well as their values and preferences, as emphasized by the 2019 AHA/ACC/HRS guideline 1 and the 2020 Kidney International overview 1.

From the FDA Drug Label

In pharmacokinetic studies, compared to healthy adult subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44 to 64% in adult subjects with renal impairment. Nonvalvular Atrial Fibrillation Patients with Chronic Kidney Disease not on Dialysis In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 20 mg once daily Patients with CrCl <30 mL/min were not studied, but administration of XARELTO 15 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment Avoid the use of XARELTO in patients with CrCl <15 mL/min

The use of rivaroxaban in patients with Chronic Kidney Disease (CKD) requires careful consideration of the patient's renal function.

• For patients with CrCl 30 to 50 mL/min, a dose of 15 mg once daily is recommended.
• For patients with CrCl <30 mL/min, the use of rivaroxaban is not well studied, but a dose of 15 mg once daily is expected to result in similar serum concentrations to those with moderate renal impairment.
• The use of rivaroxaban is contraindicated in patients with CrCl <15 mL/min due to the increased risk of bleeding. 2

From the Research

Oral Anticoagulants in CKD

• The use of oral anticoagulants in patients with chronic kidney disease (CKD) has been studied in several research papers 3, 4, 5, 6, 7.
• Apixaban has been found to be a reasonable alternative to warfarin in patients with stage 4 or 5 CKD and receiving dialysis, with similar efficacy and a better safety profile 3.
• Direct oral anticoagulants (DOACs) have been shown to be noninferior to warfarin in preventing stroke and recurrent venous thromboembolism, with lower bleeding rates in patients with moderate CKD 4.
• A systematic review and meta-analysis found that DOACs significantly reduced the risk of stroke, systemic embolism, and venous thromboembolism by 22%, and major bleeding by 17%, compared to warfarin in patients with CKD 5.
• Apixaban has been associated with a significantly better risk reduction of stroke and major bleeding than warfarin in patients with CKD stages 4-5 5.
• Rivaroxaban and apixaban have been found to be effective and safe in patients with atrial fibrillation and stage III CKD, with apixaban 5.0 mg associated with a lower effectiveness composite risk and a similar safety risk profile compared to warfarin 6.
• Warfarin dose requirements have been found to be lower in patients with CKD and end-stage renal disease (ESRD) compared to patients with normal kidney function, with a ~20% lower dose required to maintain a therapeutic international normalized ratio (INR) 7.

Comparison of Oral Anticoagulants

• Apixaban and rivaroxaban have been compared to warfarin in patients with CKD, with apixaban found to have a better safety profile and similar efficacy 3, 6.
• DOACs have been found to be noninferior to warfarin in preventing stroke and recurrent venous thromboembolism, with lower bleeding rates in patients with moderate CKD 4.
• A systematic review and meta-analysis found that DOACs significantly reduced the risk of stroke, systemic embolism, and venous thromboembolism by 22%, and major bleeding by 17%, compared to warfarin in patients with CKD 5.

Dosing and Safety

• Warfarin dose requirements have been found to be lower in patients with CKD and ESRD compared to patients with normal kidney function, with a ~20% lower dose required to maintain a therapeutic INR 7.
• Apixaban and rivaroxaban have been found to be effective and safe in patients with atrial fibrillation and stage III CKD, with apixaban 5.0 mg associated with a lower effectiveness composite risk and a similar safety risk profile compared to warfarin 6.
• DOACs have been found to be noninferior to warfarin in preventing stroke and recurrent venous thromboembolism, with lower bleeding rates in patients with moderate CKD 4.