What are the dosing guidelines for apixaban in non‑valvular atrial fibrillation, acute deep‑vein thrombosis/pulmonary embolism, extended venous thromboembolism prevention, and post‑hip/knee replacement, including when to reduce the dose to 2.5 mg twice daily (age ≥ 80 years, weight ≤ 60 kg, or impaired renal function) and considerations for hepatic impairment and drug interactions?

Apixaban Dosing Guidelines

For non-valvular atrial fibrillation, use apixaban 5 mg twice daily as the standard dose, reducing to 2.5 mg twice daily only when the patient meets at least 2 of 3 specific criteria: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL. 1, 2, 3

Atrial Fibrillation Dosing Algorithm

Standard Dose (5 mg twice daily)

• Prescribe 5 mg twice daily for all patients who meet 0 or 1 dose-reduction criteria. 1, 2, 4
• This includes patients with moderate renal impairment (CrCl 30-59 mL/min) who do not meet the other criteria. 1, 2
• Apixaban has only 27% renal clearance, making it safer in renal impairment compared to dabigatran (80%) or rivaroxaban (66%). 1, 4, 5

Reduced Dose (2.5 mg twice daily)

• Reduce to 2.5 mg twice daily only when at least 2 of these 3 criteria are present simultaneously: 1, 2, 3
  • Age ≥80 years 1, 2
  • Body weight ≤60 kg 1, 2
  • Serum creatinine ≥1.5 mg/dL 1, 2

Critical Renal Function Thresholds

• For CrCl 15-29 mL/min (severe renal impairment): Use 2.5 mg twice daily for all patients, regardless of age or weight. 1, 2
• For end-stage renal disease on hemodialysis: Use 5 mg twice daily, reducing to 2.5 mg twice daily if age ≥80 years OR weight ≤60 kg (only 1 criterion required, not 2). 1, 2, 3
• Calculate creatinine clearance using the Cockcroft-Gault equation, not eGFR, as this method was used in clinical trials and FDA labeling. 1, 2, 4

Venous Thromboembolism Dosing

Acute DVT/PE Treatment

• Use 10 mg twice daily for the first 7 days, then 5 mg twice daily thereafter. 1, 2, 3
• No dose reduction criteria apply during acute VTE treatment, regardless of age, weight, or renal function. 1, 2

Extended-Phase VTE Prevention

• After completing at least 6 months of VTE treatment, reduce to 2.5 mg twice daily for all patients. 1, 2, 3
• This reduced dose applies universally, without requiring age, weight, or renal criteria. 1, 2

Post-Orthopedic Surgery Prophylaxis

• Use 2.5 mg twice daily for all patients after hip or knee replacement surgery. 1, 2, 3
• Start 12-24 hours after surgery. 3
• Continue for 35 days after hip replacement or 12 days after knee replacement. 3

Drug Interaction Adjustments

Strong CYP3A4 and P-glycoprotein Inhibitors

• When a patient on 5 mg twice daily requires combined P-glycoprotein and strong CYP3A4 inhibitors (ketoconazole, ritonavir, itraconazole, clarithromycin), reduce to 2.5 mg twice daily. 1, 2, 4
• If the patient is already on 2.5 mg twice daily, avoid these inhibitors entirely. 1

Strong CYP3A4 Inducers

• Avoid apixaban completely with rifampin, carbamazepine, phenytoin, or St. John's wort, as they markedly reduce apixaban levels and increase thrombotic risk. 1, 4

Hepatic Impairment Considerations

• No dose adjustment needed for mild hepatic impairment (Child-Pugh A). 3
• For moderate hepatic impairment (Child-Pugh B), dosing recommendations cannot be provided due to limited data and intrinsic coagulation abnormalities. 3
• Apixaban is not recommended for severe hepatic impairment (Child-Pugh C). 3

Monitoring Requirements

• Reassess renal function at least annually in all patients. 1, 4
• Increase monitoring frequency to every 3-6 months if CrCl <60 mL/min or during clinical deterioration. 1, 4
• Reassess body weight and renal function periodically, as changes may shift patients between dose categories. 1, 2
• No routine INR or anticoagulation monitoring is required. 4

Common Prescribing Errors to Avoid

• The most frequent error is reducing the dose based on a single criterion rather than requiring 2 criteria. Studies show 9.4-40.4% of apixaban prescriptions involve inappropriate underdosing. 4, 6
• Do not reduce the dose based solely on perceived bleeding risk, frailty, or isolated moderate CKD when formal criteria are not met. 1, 4
• Do not apply atrial fibrillation dose-reduction criteria to acute VTE treatment. 1, 2
• Do not use eGFR for dosing decisions; always calculate CrCl with Cockcroft-Gault. 1, 2, 4
• For CrCl 30-59 mL/min, maintain 5 mg twice daily unless ≥2 additional criteria are present. 1, 2, 4

Switching Between Anticoagulants

From Warfarin to Apixaban

• Stop warfarin and start apixaban when INR falls below 2.0. 1, 3

From Rivaroxaban to Apixaban

• For CrCl ≥80 mL/min: Wait 24 hours after the last rivaroxaban dose. 1
• For CrCl 50-80 mL/min: Wait 24 hours for low-risk situations; extend to 36 hours if bleeding risk is elevated. 1
• For CrCl 30-50 mL/min: Wait 24-48 hours, individualized based on bleeding risk. 1
• No bridging with heparin is required when switching directly between DOACs. 1

From Other Anticoagulants to Apixaban

• Discontinue the other anticoagulant and start apixaban at the time of the next scheduled dose. 3