What is the appropriate dose of apixaban for a patient with atrial fibrillation or venous thromboembolism, considering factors such as renal function, bleeding risk, weight, and history of liver disease?

Apixaban Dosing for Atrial Fibrillation and Venous Thromboembolism

For most patients with atrial fibrillation, the correct dose is apixaban 5 mg orally twice daily, reducing to 2.5 mg twice daily ONLY when at least 2 of the following 3 criteria are met: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL. 1

Standard Dosing Algorithm

The FDA-approved dosing for stroke prevention in nonvalvular atrial fibrillation is:

• 5 mg twice daily for patients with 0 or 1 dose-reduction criteria 1
• 2.5 mg twice daily ONLY when ≥2 of these criteria are present: 1
  • Age ≥80 years
  • Body weight ≤60 kg
  • Serum creatinine ≥1.5 mg/dL

This dosing algorithm was validated in the ARISTOTLE trial, which demonstrated that patients with only 1 dose-reduction criterion who received 5 mg twice daily had similar efficacy (HR 0.94 for stroke) and safety (HR 0.68 for major bleeding) compared to warfarin as those with no dose-reduction criteria. 2

Renal Function Considerations

Calculate creatinine clearance using the Cockcroft-Gault equation, NOT eGFR, as this was the method used in clinical trials and FDA labeling. 3, 4

Dosing by Renal Function:

• CrCl >50 mL/min: Standard 5 mg twice daily (unless ≥2 dose-reduction criteria met) 3
• CrCl 30-50 mL/min: Standard 5 mg twice daily (unless ≥2 dose-reduction criteria met) 3, 4
• CrCl 15-29 mL/min: Use 2.5 mg twice daily with caution 3
• CrCl <15 mL/min (not on dialysis): Contraindicated 3
• End-stage renal disease on hemodialysis: 5 mg twice daily, reduced to 2.5 mg twice daily if age ≥80 years OR body weight ≤60 kg (note: only ONE criterion needed in dialysis patients, not two) 3, 1

Apixaban has only 27% renal clearance, making it safer in renal impairment compared to dabigatran (80% renal) or rivaroxaban (66% renal). 4 This pharmacokinetic profile provides a safety margin in moderate chronic kidney disease. 4

Critical Pitfall to Avoid:

The most common prescribing error is inappropriate dose reduction based on a single criterion rather than requiring two. 5 Studies show 9.4-40.4% of apixaban prescriptions involve underdosing, often driven by clinician concern about renal function or perceived bleeding risk when formal criteria are not met. 4 For example, a patient with CrCl 44 mL/min (moderate renal impairment) but age 65 years and weight 75 kg should receive 5 mg twice daily, NOT 2.5 mg twice daily. 4

Venous Thromboembolism Dosing

For acute DVT/PE treatment: 1

• 10 mg twice daily for 7 days, then
• 5 mg twice daily for 6 months

For extended VTE prophylaxis (after completing initial 6-month treatment): 1

• 2.5 mg twice daily

For VTE prophylaxis after hip/knee replacement: 1

• 2.5 mg twice daily starting 12-24 hours post-surgery
• Duration: 35 days (hip) or 12 days (knee)

Drug Interactions Requiring Dose Adjustment

Reduce apixaban from 5 mg to 2.5 mg twice daily when using combined P-glycoprotein AND strong CYP3A4 inhibitors: 4

• Ketoconazole
• Ritonavir
• Itraconazole

Avoid apixaban entirely with strong CYP3A4 inducers (e.g., rifampin), as they reduce apixaban levels significantly. 4

Monitoring Requirements

Reassess renal function: 4

• At least annually for all patients
• Every 3-6 months if CrCl <60 mL/min
• More frequently if clinical deterioration occurs

No routine INR or anticoagulation monitoring is required. 4

Switching Between Anticoagulants

From warfarin to apixaban: 1

• Discontinue warfarin
• Start apixaban when INR <2.0
• No bridging therapy needed

From apixaban to warfarin: 1

• Discontinue apixaban
• Begin BOTH parenteral anticoagulant (heparin/LMWH) AND warfarin at the time of next scheduled apixaban dose
• Continue parenteral anticoagulant until INR reaches therapeutic range

From other DOACs to apixaban: 1

• Simply discontinue the other DOAC
• Start apixaban at the time the next dose of previous DOAC would have been due

Perioperative Management

Hold apixaban before surgery based on bleeding risk and renal function: 4

If CrCl >25 mL/min: 4

• Low bleeding risk procedures: Hold 1 day (24 hours)
• High bleeding risk procedures: Hold 2 days (48 hours)

If CrCl <25 mL/min: 4

• Consider holding an additional 1-3 days, especially for high bleeding risk procedures

Restart apixaban as soon as adequate hemostasis is established. 1 Bridging anticoagulation during the 24-48 hours after stopping apixaban is not generally required. 1

Special Populations

Liver Disease:

Avoid apixaban in patients with: 6

• Transaminases >2 times upper limit of normal
• Total bilirubin >1.5 times upper limit of normal

Apixaban is primarily metabolized via the liver (CYP3A4-dependent), with renal elimination accounting for only 27% of total clearance. 6

Cancer Patients:

Current guidelines do not recommend apixaban for VTE treatment or prophylaxis in cancer patients due to insufficient clinical data. 6 Only 2.7% of patients in the AMPLIFY trial had active cancer. 6

Patients with PCI or ACS:

For patients with atrial fibrillation undergoing PCI, use apixaban with clopidogrel (without aspirin) after a brief periprocedural period to reduce bleeding risk. 6, 3 In the AUGUSTUS trial, apixaban 5 mg twice daily (reduced to 2.5 mg twice daily if ≥2 criteria met) demonstrated lower bleeding rates compared to VKA without increased ischemic events. 6, 7

Evidence Supporting Dosing in Severe Renal Impairment

While landmark trials excluded patients with CrCl <25 mL/min, recent real-world data suggest apixaban may be reasonable in severe renal dysfunction. 8 A multicenter retrospective study found that apixaban had a lower risk of combined thrombotic and bleeding events compared to warfarin in patients with CrCl <25 mL/min (HR 0.47,95% CI 0.25-0.92). 8 However, another study found no difference in bleeding rates between 5 mg and 2.5 mg twice daily dosing in patients with stage 4-5 CKD, including those on hemodialysis. 9

Missed Dose Protocol

If a dose is missed, take it as soon as possible on the same day and resume twice-daily administration. 1 Do not double the dose to make up for a missed dose. 1 Apixaban has a 12-hour half-life, and missed doses can increase thromboembolic risk. 3