What are the indications, dosing regimens, monitoring requirements, contraindications, and reversal options for Eliquis (apixaban)?

Eliquis (Apixaban): Clinical Overview

Eliquis (apixaban) is a direct factor Xa inhibitor approved for stroke prevention in nonvalvular atrial fibrillation, VTE prophylaxis after orthopedic surgery, and treatment/prevention of venous thromboembolism, with standard dosing of 5 mg twice daily for atrial fibrillation (reduced to 2.5 mg twice daily if ≥2 criteria: age ≥80 years, weight ≤60 kg, or serum creatinine ≥1.5 mg/dL) and no routine monitoring required. 1

Approved Indications

Apixaban is FDA-approved for the following conditions 1:

• Stroke prevention in nonvalvular atrial fibrillation: Reduces risk of stroke and systemic embolism 1
• VTE prophylaxis after major orthopedic surgery: Following hip or knee replacement 2, 1
• Treatment of acute DVT and PE: Initial and extended therapy 1
• Reduction of recurrent DVT/PE risk: Following initial treatment 1

Dosing Regimens

Atrial Fibrillation

• Standard dose: 5 mg orally twice daily 2, 1
• Reduced dose: 2.5 mg orally twice daily if patient meets at least 2 of the following criteria: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL (133 μmol/L) 2, 1

VTE Treatment

• Initial treatment: 10 mg orally twice daily for 7 days 2, 1
• Continued treatment: 5 mg orally twice daily after initial 7 days 2, 1
• Extended prevention: 2.5 mg orally twice daily for reduction of recurrent VTE 2, 1

Orthopedic Surgery Prophylaxis

• Dose: 2.5 mg orally twice daily 2, 1
• Duration: 5 weeks for total hip replacement, 2 weeks for total knee replacement 2

Pharmacokinetic Profile

Apixaban demonstrates predictable pharmacokinetics 3, 4:

• Bioavailability: Approximately 50% oral bioavailability 2, 3
• Time to peak levels: 3-4 hours after oral administration 2, 3
• Half-life: 8-14 hours (approximately 12 hours) 2, 3
• Elimination: Multiple pathways including metabolism, biliary excretion, and direct intestinal excretion; 27% renal clearance 2, 3
• Metabolism: Via CYP3A4-dependent and independent pathways 2

Monitoring Requirements

No routine anticoagulation monitoring is required 1, 5, 4. This represents a major advantage over warfarin, as apixaban has predictable pharmacodynamics and pharmacokinetics 5, 4.

However, specific situations may warrant assessment 2:

• Renal function: Assess creatinine clearance using Cockcroft-Gault formula, particularly before surgery or in elderly patients 2
• Bleeding complications: If major bleeding occurs, biological monitoring of drug concentration may be considered 2

Contraindications

Apixaban is contraindicated in 1:

• Active pathological bleeding 1
• Severe hypersensitivity to apixaban 1
• Prosthetic heart valves: Use not recommended 1
• Triple positive antiphospholipid syndrome: Use not recommended due to increased thrombotic risk 1
• Pregnancy: Not recommended 2, 1
• Severe hepatic impairment: Not recommended 1

Drug Interactions Requiring Dose Adjustment

Combined P-glycoprotein and Strong CYP3A4 Inhibitors

Reduce apixaban dose or avoid coadministration with potent dual inhibitors such as ketoconazole or ritonavir, as they significantly increase plasma drug concentrations 2, 1.

Combined P-glycoprotein and Strong CYP3A4 Inducers

Avoid concomitant use, as these agents reduce apixaban blood levels and anticoagulant effect 1.

Perioperative Management

Low Bleeding Risk Procedures

For procedures with low hemorrhagic risk 2:

• Last dose timing:
  • If twice daily regimen: last intake on the morning of the day before the procedure 2
  • If once daily morning regimen: last dose on the morning of the day before the procedure 2
  • If once daily evening regimen: last dose two days before the procedure 2
• No bridging anticoagulation required 2
• Resumption: At least 6 hours after procedure if hemostasis achieved 2

High Bleeding Risk Procedures

For procedures with high hemorrhagic risk 2:

• Interruption timing: 3 days before procedure when creatinine clearance >30 mL/min 2
• Very high risk procedures (intracranial neurosurgery, neuraxial anesthesia): Up to 5 days interruption 2
• No preoperative heparin bridging except for very high thrombotic risk patients 2

Critical Perioperative Warnings

Do not perform spinal or epidural anesthesia or deep-block techniques in patients with possible DOAC concentration (insufficient discontinuation time) 2. Epidural or spinal hematomas may result in long-term or permanent paralysis 1.

Reversal Options

Specific Reversal Agent

Andexanet alfa is the specific reversal agent for apixaban 2:

• Low dose regimen: 400 mg IV bolus over 15 minutes, followed by 480 mg infusion over 2 hours 2
• High dose regimen: 800 mg IV bolus over 30 minutes, followed by 960 mg infusion over 2 hours 2
• Indication: Life-threatening, uncontrolled bleeding with dosable plasma DOAC levels 2

Alternative Hemostatic Measures

If andexanet alfa is unavailable 2:

• Prothrombin complex concentrate (PCC): High-dose (25-50 U/kg) may be administered for life-threatening bleeding 2
• Measurement: Substrate-specific anti-factor Xa activity can be measured to guide reversal decisions 2

When to Consider Reversal

Reversal should be considered 2:

• Serious bleeding with DOAC level >50 ng/mL 2
• Invasive procedure with high bleeding risk and DOAC level >30 ng/mL 2
• Hemorrhagic shock not responding to resuscitation 2

Switching Between Anticoagulants

From Dabigatran to Apixaban

Discontinue dabigatran and begin apixaban when the next scheduled dose of dabigatran would be due, with no overlap, no gap, and no bridging anticoagulation required 6.

From Apixaban to Warfarin

Start warfarin at usual initial dose (typically 5 mg daily) and simultaneously begin parenteral anticoagulant (LMWH or UFH) at the time of the next scheduled apixaban dose 7. Continue both warfarin and parenteral anticoagulant for at least 5 days, stopping the parenteral agent only when INR ≥2.0 for at least 24 hours 7.

Common Pitfalls and Caveats

Bleeding Risk

• Most common adverse reactions (>1%) are bleeding-related 1
• Apixaban demonstrated superior bleeding profile compared to warfarin, with significantly lower rates of major bleeding, intracranial hemorrhage, and hemorrhagic stroke 2, 5
• Gastrointestinal bleeding rates were similar to warfarin 2

Premature Discontinuation

Premature discontinuation increases risk of thrombotic events; consider coverage with another anticoagulant if apixaban is discontinued for reasons other than pathological bleeding or completion of therapy 1.

Renal Impairment

• Apixaban has 27% renal clearance, making it preferable in moderate renal impairment compared to dabigatran (80% renal elimination) 2, 3
• Assess creatinine clearance before initiating therapy and periodically thereafter 2

Drug Switching Errors

• Never overlap DOACs, as this creates excessive anticoagulation and bleeding risk 6
• Never leave a gap between stopping one DOAC and starting another, as this creates inadequate anticoagulation and thrombotic risk 6

Special Populations

• Pregnancy and lactation: Discontinue drug or discontinue nursing 1
• Elderly patients: Consider extended interruption periods (72 hours) in patients over 80 years for high-risk procedures 8
• Concomitant antiplatelet therapy: In acute coronary syndrome, apixaban added to dual antiplatelet therapy resulted in unacceptably high bleeding rates 4