Apixaban (Eliquis) Clinical Guide
Dosing Recommendations
Atrial Fibrillation - Stroke Prevention
The standard dose for stroke prevention in nonvalvular atrial fibrillation is apixaban 5 mg orally twice daily. 1
Dose reduction to 2.5 mg twice daily is required when ANY TWO of the following criteria are met: 1
- Age ≥80 years
- Body weight ≤60 kg
- Serum creatinine ≥1.5 mg/dL
Apixaban demonstrated superiority over warfarin in the ARISTOTLE trial, reducing stroke/systemic embolism from 1.60% to 1.27% per year (HR 0.79, P<0.01), with significantly less major bleeding (2.13% vs 3.09%, P<0.001) and lower all-cause mortality (3.52% vs 3.94%, P=0.047). 2
Apixaban was also superior to aspirin in the AVERROES trial for patients unsuitable for warfarin, reducing stroke/systemic embolism from 3.6% to 1.6% (RR 0.46) without increasing major bleeding. 2
Venous Thromboembolism Treatment
For acute DVT/PE treatment, apixaban 10 mg orally twice daily for 7 days, then 5 mg twice daily for at least 3-6 months. 1
Apixaban is now a strongly recommended option for VTE treatment in cancer patients, with high-quality evidence demonstrating effectiveness in reducing recurrent VTE with low major bleeding risk. 2
For extended secondary prevention after completing initial VTE treatment, apixaban 2.5 mg twice daily can be used to reduce recurrence risk. 1
Postoperative Thromboprophylaxis
For hip replacement surgery: apixaban 2.5 mg orally twice daily for 35 days (5 weeks), starting 12-24 hours after surgery. 2, 3
For knee replacement surgery: apixaban 2.5 mg orally twice daily for 10-14 days, starting 12-24 hours after surgery. 2, 4
Apixaban demonstrated superiority over enoxaparin 40 mg daily in the ADVANCE-2 (knee) and ADVANCE-3 (hip) trials, with lower VTE rates and similar or reduced bleeding. 2
Apixaban and rivaroxaban are now added as options for extended pharmacologic thromboprophylaxis after cancer surgery, though with weak strength of recommendation due to trial limitations. 2
Contraindications
Absolute contraindications include: 1
- Active pathological bleeding
- Severe hypersensitivity reaction to apixaban
Clinical contraindications based on guideline evidence: 2
- Concomitant use with potent dual inhibitors of both CYP3A4 AND P-glycoprotein (ketoconazole, ritonavir, clarithromycin, itraconazole)
- Prosthetic heart valves (apixaban is not indicated and may be harmful) 1
- Hemodynamically unstable PE patients requiring thrombolysis or pulmonary embolectomy 1
- Triple-positive antiphospholipid syndrome (increased thrombosis risk) 1
Drug Interactions
Major Interactions Requiring Dose Adjustment or Avoidance
Combined strong CYP3A4 AND P-glycoprotein inhibitors are contraindicated as they significantly increase apixaban plasma concentrations. 2, 1
Combined strong CYP3A4 AND P-glycoprotein inducers (rifampin, phenytoin, carbamazepine, St. John's wort) should be avoided as they reduce apixaban levels by approximately 50%, compromising efficacy. 1
Anticoagulants and Antiplatelet Agents
- Concomitant use with other anticoagulants, antiplatelet agents, NSAIDs, or SSRIs increases bleeding risk and requires careful assessment. 1
- In acute coronary syndrome patients, adding apixaban 5 mg twice daily to dual antiplatelet therapy did not show favorable risk/benefit due to increased bleeding. 5
Monitoring Requirements
Apixaban does not require routine laboratory monitoring for dose adjustment, unlike warfarin. 6, 7
When Monitoring May Be Useful
- Renal function should be monitored postoperatively as surgical stress may affect kidney function and apixaban clearance. 8, 3
- Approximately 27% of apixaban clearance occurs via renal excretion, making renal function relevant in dose adjustment decisions. 6
- In very high-risk situations (neurosurgery, cardiac surgery, severe renal insufficiency), plasma level measurement may be considered though not routinely available. 2
Pharmacokinetic Profile
- Peak plasma concentration occurs 3-4 hours after oral administration. 2, 6
- Terminal half-life is 8-14 hours (approximately 12 hours). 2, 6
- Oral bioavailability is approximately 50%, and food does not have clinically meaningful impact. 6
Perioperative Management
Preoperative Discontinuation
For most elective surgeries with standard bleeding risk, discontinue apixaban 48 hours before the procedure. 2
For high bleeding risk procedures (neurosurgery, spinal surgery, major cardiac surgery), discontinue apixaban 72-120 hours (3-5 days) before surgery. 2, 8
Factors Requiring Extended Discontinuation
- Creatinine clearance 30-50 mL/min requires longer discontinuation periods beyond standard 48 hours. 8, 4
- Age ≥80 years, concomitant P-glycoprotein inhibitors, or body weight <50 kg may require +24 hours additional interruption time. 2, 8
- Calculate creatinine clearance using Cockcroft-Gault formula to guide timing. 8
Neuraxial Anesthesia Considerations
Do NOT perform spinal or epidural anesthesia if there is any possibility of residual apixaban concentration from insufficient discontinuation time. 8
- For neuraxial procedures, interruption times up to 5 days may be needed, especially in elderly patients or those with renal impairment. 8, 4
- If an epidural catheter is placed, therapeutic anticoagulation must be delayed until after catheter removal. 4
Bridging Anticoagulation
Preoperative bridging with heparin is NOT indicated for most patients, as it increases bleeding risk without reducing thrombotic complications. 8, 3
- Bridging is only recommended for patients at very high thrombotic risk. 8
Postoperative Resumption
For low-to-moderate bleeding risk surgery, resume apixaban at full therapeutic dose 24 hours after surgery once adequate hemostasis is established. 3
For high bleeding risk surgery (major orthopedic, thoracic, extensive dissection), delay resumption to 48-72 hours after surgery. 2, 3
Immediate Postoperative VTE Prophylaxis
- If VTE prophylaxis is needed immediately post-surgery, heparin or fondaparinux can be administered at least 6 hours after the procedure. 8, 3, 4
- For high thrombotic risk patients, consider starting with reduced dose apixaban 2.5 mg twice daily for 2-3 days, then increase to full therapeutic dose. 3
Critical Pitfall to Avoid
Never resume full-dose apixaban within 24 hours after high bleeding risk surgery, as this significantly increases major bleeding risk. 3
Reversal Options
Andexanet alfa is the specific reversal agent for apixaban and other oral factor Xa inhibitors, currently undergoing phase III investigation. 2
Reversal Agent Mechanisms
- Andexanet alfa is a modified recombinant factor Xa molecule that binds factor Xa inhibitors with high affinity, reversing their anticoagulant effects. 2
- Idarucizumab is specific for dabigatran only and does NOT reverse apixaban. 2
- Ciraparantag (PER977) is reported to reverse all DOACs but is at an earlier stage of development. 2
Clinical Context
- Outcomes of major bleeds with apixaban are no worse than with warfarin even in the absence of clinically available antidotes. 2
- Apixaban is associated with significantly less life-threatening bleeding, particularly intracranial hemorrhage, compared to warfarin. 2
Special Populations
Renal Impairment
- For atrial fibrillation patients with creatinine clearance 15-29 mL/min, reduce dose to 2.5 mg twice daily. 1
- Apixaban is not recommended when creatinine clearance is <15 mL/min or in patients on dialysis for atrial fibrillation indication. 1
- Renal function significantly impacts apixaban elimination and must guide both dosing and perioperative discontinuation timing. 8
Elderly Patients
- Age ≥80 years is one criterion for dose reduction in atrial fibrillation (when combined with other factors). 1
- Elderly patients require careful consideration before neuraxial techniques due to higher risk of residual drug concentration. 8