Until what Glomerular Filtration Rate (GFR) do Direct Oral Anticoagulants (DOACs) have FDA approval?

FDA Approval of DOACs Based on GFR

Direct Oral Anticoagulants (DOACs) have FDA approval for use down to a GFR of 15 mL/min, with specific dosing adjustments required below 30 mL/min. 1

FDA Approval Status by DOAC and Renal Function

Creatinine Clearance 15-30 mL/min:

• Apixaban: FDA approved at 5 mg BID or 2.5 mg BID (if ≥2 of: age ≥80 years, weight ≤60 kg, or serum creatinine ≥1.5 mg/dL) 1
• Rivaroxaban: FDA approved at 15 mg once daily 1
• Edoxaban: FDA approved at 30 mg once daily 1
• Dabigatran: FDA approved at 75 mg BID (based solely on pharmacokinetic data, not clinical outcomes) 1

Creatinine Clearance <15 mL/min (non-dialysis):

• Apixaban: FDA approved at 5 mg BID 1
• Rivaroxaban: Limited clinical data - 15 mg once daily 1
• Edoxaban: Not FDA approved 1
• Dabigatran: Not FDA approved 1

Dialysis patients:

• Apixaban: FDA approved at 5 mg BID 1
• Rivaroxaban: Limited clinical data - 15 mg once daily 1
• Edoxaban: Not FDA approved 1
• Dabigatran: Not FDA approved 1

Important Clinical Considerations

Renal Function Assessment

• FDA approval is based on creatinine clearance (CrCl) using the Cockcroft-Gault equation, not eGFR 1, 2
• Using eGFR equations (MDRD-4 or CKD-EPI) instead of CrCl can lead to significant dosing discrepancies, particularly in:
  • Elderly patients (≥75 years) 2
  • Patients with borderline renal function (CrCl <60 mL/min) 2
  • Females 3

Clinical Evidence in CKD

• In mild to moderate CKD (eGFR 30-59 mL/min), DOACs have shown similar efficacy with superior safety compared to vitamin K antagonists 1, 4
• Recent evidence suggests apixaban may have the most favorable safety profile in patients with reduced kidney function (eGFR 15-30 mL/min) 4
• For patients with eGFR 30-49 mL/min, apixaban was associated with lower bleeding risk compared to rivaroxaban (78% higher relative risk with rivaroxaban) 4

Common Pitfalls

• Using eGFR instead of CrCl for DOAC dosing decisions can result in:
  • Overdosing in up to 59.2% of patients 3
  • Underdosing in up to 28.8% of patients 3
• DOACs accumulate in severe renal impairment, increasing bleeding risk 5
• Regular monitoring of renal function is essential in all patients on DOACs, especially those with fluctuating renal function 1, 6

European vs. FDA Approval

• European Medicines Agency (EMA) is more restrictive than FDA:
  • All DOACs are contraindicated by EMA for CrCl <15 mL/min 1
  • Dabigatran is contraindicated by EMA for CrCl <30 mL/min 1
  • All DOACs are contraindicated by EMA for dialysis patients 1

Despite FDA approval in some cases of severe renal impairment, clinical evidence supporting DOAC use in these populations is limited, and careful risk-benefit assessment is warranted 1.