What are the dosage recommendations for Direct Oral Anticoagulants (DOACs) initiation and continuation based on Glomerular Filtration Rate (GFR) levels?

From the Guidelines

The dosage recommendations for Direct Oral Anticoagulants (DOACs) should be adjusted based on a patient's glomerular filtration rate (GFR), with specific adjustments required as kidney function declines, as outlined in the 2024 ESC guidelines for the management of atrial fibrillation 1.

Key Considerations for DOAC Dosage Adjustment

• For apixaban, the standard dose is 5 mg twice daily, but should be reduced to 2.5 mg twice daily if the patient has at least two of the following: age ≥80 years, weight ≤60 kg, or serum creatinine ≥133 mmol/L.
• For rivaroxaban, the typical dose for atrial fibrillation is 20 mg daily with food, reduced to 15 mg daily when GFR is 15-49 mL/min.
• For dabigatran, the dose reduction is recommended if any of the following apply: age ≥80 years, receiving concomitant verapamil, or moderate renal impairment (creatinine clearance 30-50 mL/min).
• For edoxaban, the dose reduction is recommended if any of the following apply: moderate or severe renal impairment (creatinine clearance 15-50 mL/min), body weight ≤60 kg, or concomitant use of certain medications.

Importance of Regular Renal Function Monitoring

Regular monitoring of renal function is essential, particularly in elderly patients or those with fluctuating kidney function, as dosage adjustments may be necessary if GFR changes significantly, as emphasized in the 2018 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation 1.

Clinical Decision-Making

Clinical decisions on how to treat an AF patient with CKD who needs OAC requires the assessment of renal function, and the use of equations such as the CKD-EPI equation or the Cockcroft-Gault method to estimate renal function, as discussed in the 2018 European Heart Rhythm Association practical guide 1.

Additional Considerations

Other variables that may impact the choice of anticoagulant therapy for individual patients include the cost of the DOACs, patient preference for once- or twice-daily dosing, and the presence of conditions that may influence medication absorption, as noted in the 2020 American Society of Hematology guidelines for management of venous thromboembolism 1.

From the FDA Drug Label

In ARISTOTLE, patients were randomized to apixaban 5 mg orally twice daily (or 2. 5 mg twice daily in subjects with at least 2 of the following characteristics: age greater than or equal to 80 years, body weight less than or equal to 60 kg, or serum creatinine greater than or equal to 1.5 mg/dL)

The dosage recommendations for apixaban, a Direct Oral Anticoagulant (DOAC), are as follows:

• Initiation and continuation: 5 mg orally twice daily
• Adjusted dosage: 2.5 mg twice daily in subjects with at least 2 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 2

From the Research

Dosage Recommendations for DOACs Based on GFR Levels

The dosage recommendations for Direct Oral Anticoagulants (DOACs) initiation and continuation are based on the patient's Glomerular Filtration Rate (GFR) levels.

• The GFR is estimated using various formulas, including the Modification of Diet in Renal Disease (MDRD) and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations 3, 4.
• Studies have shown that cystatin C is a more sensitive marker than creatinine for estimating GFR, especially in patients with early stages of renal impairment 3.
• The dosage of DOACs, such as apixaban, dabigatran, and rivaroxaban, should be adjusted based on the patient's GFR level to minimize the risk of bleeding and ensure effective anticoagulation 5, 6.
• For example, apixaban is recommended at a dose of 5 mg twice daily for patients with a GFR of 50 mL/min or higher, while a dose reduction to 2.5 mg twice daily is recommended for patients with a GFR of 30-49 mL/min 5.
• Similarly, dabigatran is recommended at a dose of 150 mg twice daily for patients with a GFR of 50 mL/min or higher, while a dose reduction to 75 mg twice daily is recommended for patients with a GFR of 30-49 mL/min 5.
• Rivaroxaban is recommended at a dose of 20 mg once daily for patients with a GFR of 50 mL/min or higher, while a dose reduction to 15 mg once daily is recommended for patients with a GFR of 30-49 mL/min 5.

GFR-Based Dosage Adjustments for DOACs

The following are the GFR-based dosage adjustments for DOACs:

• Apixaban:
  • GFR ≥ 50 mL/min: 5 mg twice daily
  • GFR 30-49 mL/min: 2.5 mg twice daily
• Dabigatran:
  • GFR ≥ 50 mL/min: 150 mg twice daily
  • GFR 30-49 mL/min: 75 mg twice daily
• Rivaroxaban:
  • GFR ≥ 50 mL/min: 20 mg once daily
  • GFR 30-49 mL/min: 15 mg once daily

Importance of Accurate GFR Estimation

Accurate estimation of GFR is crucial for determining the appropriate dosage of DOACs, as incorrect dosing can increase the risk of bleeding or thromboembolic events 4, 7.

• Studies have shown that the use of cystatin C-based GFR estimation equations can provide more accurate results than creatinine-based equations, especially in patients with early stages of renal impairment 3, 7.
• The full-age-spectrum (FAS) equation has been developed for use in elderly patients and has been shown to provide more accurate results than other GFR estimation equations 7.