Apixaban (Eliquis)


Indications

Systemic Embolism Prevention in Nonvalvular Atrial Fibrillation (see Atrial Fibrillation)

Clinical Efficacy-General

  • FDA Approved in December, 2012 for Stroke Prevention in Non-Valvular Atrial Fibrillation
  • AVERROES Trial (NEJM, 2011) [MEDLINE]
    • In Patients with Atrial Fibrillation for Whom Coumadin Therapy was Not Suitable, Apixaban Decreased the Risk of Stroke and Systemic Embolism without Significantly Increasing the Risk of Major Bleeding or Intracranial Hemorrhage
  • Systematic Review of Novel Oral Anticoagulants, As Compared to Coumadin (Ann Intern Med, 2012) [MEDLINE]: included chronic non-valvular atrial fibrillation trials (RE-LY Trial (2009): dabigatran, ARISTOTLE Trial (2011): apixaban, ROCKET AF Trial (2011): rivaroxaban) and venous thromboembolism trials (EINSTEIN-DVT (2010): rivaroxaban, RE-COVER (2009): dabigatran, EINSTEIN-PE (2012): rivaroxaban)
    • Direct Oral Anticoagulants Decreased All-Cause Mortality, as Compared to Coumadin: risk ratio [RR], 0.88 [95% CI, 0.82 to 0.96]
    • Direct Oral Anticoagulants are a Viable Option for Patients Requiring Long-Term Anticoagulation, Although the Treatment Benefits Compared with Coumadin are Small and Vary Depending on the Control Achieved by Coumadin Treatment
  • Systematic Review and Meta-Analysis of Bleeding Complications with DOAC’s in Atrial Fibrillation and Venous Thromboembolism (Blood. 2014) [MEDLINE]
    • DOAC’s were Associated with Less Major Bleeding Less Fatal Bleeding, Less Intracranial Bleeding, Less Clinically Relevant Bleeding, and Less Total Bleeding, as Compared to Coumadin
  • Systematic Review and Meta-Analysis of Mortality Outcomes of DOAC’s in Patients with Atrial Fibrillation and Venous Thromboembolism (J Thromb Haemost, 2015) [MEDLINE]
    • DOAC’s were Associated with a Lower Rate of Fatal Bleeding, Lower Case-Fatality Rate of Major Bleeding, Decreased Cardiovascular Mortality, and Decreased All-Cause Mortality, as Compared to Coumadin

Clinical Efficacy-Cost-Effectiveness

  • Systematic Review of Cost-Effectiveness of Novel Oral Anticoagulants for Stroke Prevention in Non-Valvular Atrial Fibrillation (Rev Port Cardiol, 2015) [MEDLINE]
    • Direct Oral Anticoagulants are Cost-Effective for Stroke Prevention in Atrial Fibrillation, as Compared to Coumadin
  • Review of Cost-Effectiveness of Novel Oral Anticoagulants for Stroke Prevention in Non-Valvular Atrial Fibrillation (Curr Cardiol Rep, 2015) [MEDLINE]
    • Direct Oral Anticoagulants are Cost-Effective for Stroke Prevention in Atrial Fibrillation, as Compared to Coumadin

Venous Thromboembolism (see Deep Venous Thrombosis and Acute Pulmonary Embolism)

Clinical Efficacy

  • Apixaban was FDA Approved in August, 2014 for the Treatment of Venous Thromboembolism
  • Systematic Review of Novel Oral Anticoagulants, As Compared to Coumadin (Ann Intern Med, 2012) [MEDLINE]: included chronic non-valvular atrial fibrillation trials (RE-LY Trial (2009): dabigatran, ARISTOTLE Trial (2011): apixaban, ROCKET AF Trial (2011): rivaroxaban) and venous thromboembolism trials (EINSTEIN-DVT (2010): rivaroxaban, RE-COVER (2009): dabigatran, EINSTEIN-PE (2012): rivaroxaban)
    • Direct Oral Anticoagulants Decreased All-Cause Mortality, as Compared to Coumadin: risk ratio [RR], 0.88 [95% CI, 0.82 to 0.96]
    • Direct Oral Anticoagulants are a Viable Option for Patients Requiring Long-Term Anticoagulation, Although the Treatment Benefits Compared with Coumadin are Small and Vary Depending on the Control Achieved by Coumadin Treatment
  • AMPLIFY (Apixaban for Treatment of Acute Venous Thromboembolism) Trial Comparing Conventional Heparin/Coumadin vs Apixaban in the Treatment of Acute DVT-PE (NEJM, 2013) [MEDLINE]: Bristol-Myers Squibb and Pfizer-funded randomized, double-blind study (n = 5395) comparing apixaban (10 mg BID x7 days, followed by 5 mg BID x6 mo) with conventional therapy (subcutaneous enoxaparin, followed by warfarin)
    • Fixed-Dose Apixaban was Non-Inferior to Conventional Heparin/Coumadin for the Treatment of Acute DVT/PE
    • Apixaban was Associated with Significantly Less Risk of Hemorrhage, as Compared to Conventional Heparin/Coumadin
      • Major Bleeding Occurred in 0.6% of Apixaban Patients, as Compared to 1.8% of Heparin/Coumadin Patients: relative risk: 0.31 (95% CI, 0.17 to 0.55; p<0.001 for superiority)
      • Composite Outcome of Major Bleeding and Clinically-Relevant No-Major Bleeding Occurred in 4.3% of Apixaban Patients, as Compared to 9.7% of Heparin/Coumadin Patients: relative risk: 0.44 (95% CI, 0.36 to 0.55; p<0.001)
  • AMPLIFY-EXT Trial (Apixaban After the Initial Management of Pulmonary Embolism and Deep Venous Thrombosis with First-Line Therapy-Extended Treatment) (NEJM, 2013) [MEDLINE]: randomized, controlled trial (funded by Bristol-Myers Squibb and Pfizer) of patients with DVT (75%) and PE (25%), all of whom had received 6-12 mo of anticoagulation with resolution (n = 842: apixaban 2.5 mg BID x 12 mo; n = 815: apixaban 5 mg BID x 12 mo; n = 829: placebo BID x 12 mo)
    • Demographics: average age 56 y/o, <10% of the patients had a transient or reversible risk factor, and only 2% of patients had active cancer
    • Apixaban Decreased All-Cause Mortality Rate: 0.8% in 2.5 mg group, 0.5% in 5 mg group, and 1.7% in placebo group
    • Apixaban Decreased Symptomatic Recurrent Venous Thromboembolism or Mortality Rate from Venous Thromboembolism: 1.7% in apixaban groups vs 8.8% in placebo group
    • Apixaban Decreased the Risk of Major Bleeding: 0.2% in 2.5 mg group, 0.1% in 5 mg group, and 0.5% in placebo group
    • Apixaban Increased the Risk of Clinically-Relevant Non-Major Bleeding: 3% in 2.5 mg group, 4.2% in 5 mg group, and 2.3% in placebo group
  • Cochrane Systematic Review and Meta-Analysis of DOAC’s (Dabigatran, Rivaroxaban, Apixaban, and Edoxaban) in the Treatment of Acute Symptomatic Venous Thromboembolism (J Thromb Haemost, 2014) [MEDLINE]
    • DOAC’s Have Comparable Efficacy to Coumadin and are Associated with a Significantly Lower Risk of Hemorrhagic Complications (Although the Number Needed to Treatment to Prevent One Major Bleed was Notably High at 149)
  • Systematic Review and Meta-Analysis of Bleeding Complications with DOAC’s in Atrial Fibrillation and Venous Thromboembolism (Blood. 2014) [MEDLINE]
    • DOAC’s were Associated with Less Major Bleeding Less Fatal Bleeding, Less Intracranial Bleeding, Less Clinically Relevant Bleeding, and Less Total Bleeding, as Compared to Coumadin
  • Systematic Review and Meta-Analysis of Mortality Outcomes of DOAC’s in Patients with Atrial Fibrillation and Venous Thromboembolism (J Thromb Haemost, 2015) [MEDLINE]
    • DOAC’s were Associated with a Lower Rate of Fatal Bleeding, Lower Case-Fatality Rate of Major Bleeding, Decreased Cardiovascular Mortality, and Decreased All-Cause Mortality, as Compared to Coumadin

Deep Venous Thrombosis (DVT) Prophylaxis in Medical Patients (see Deep Venous Thrombosis)

Clinical Efficacy

  • ADOPT Trial Examining Prolonged Apixaban (x 30 Days) vs Enoxaparin (x At Least 6 Days) for DVT Prophylaxis After Hospital Discharge in Medical Patients (NEJM, 2011) [MEDLINE]: double-blind, double-dummy, placebo-controlled trial (n = 6528)
    • In Medically Ill Patients, an Extended Course of Apixaban DVT Prophylaxis was not Superior to a Shorter Course of Enoxaparin
    • Apixaban was Associated with Significantly More Major Bleeding Events (0.47%) than Enoxaparin (0.19%) at Day 30

Venous Thromboembolism Prophylaxis Post-Knee and Hip Replacement (see Deep Venous Thrombosis)

Clinical Efficacy

  • FDA Approved in March, 2014 for DVT Prophylaxis After Hip/Knee Replacement
  • Systematic Review Comparing Novel Oral and Other Anticoagulants (Fondaparinux, Dabigatran, Rivaroxaban, Apixaban) to Enoxaparin Used as Venous Thromboembolism Prophylaxis After Major Orthopedic Surgery (Ann Vasc Surg, 2013) [MEDLINE]
    • Direct Anticoagulants Can Be Considered as Alternatives to Enoxaparin, Depending on Their Individual Clinical Characteristics and Cost-Effectiveness
    • Primary Efficacy (Any DVT, Non-Fatal PE, or All-Cause Mortality) Favored Fondaparinux and Rivaroxaban Over Enoxaparin
    • Compared to Enoxaparin, the Bleeding Risk was Similar for All Agents, Except Fondaparinux (Which Manifested a Significantly Higher Any-Bleeding Risk) and Apixaban (Which Manifested a Lower Any-Bleeding Risk)

Pharmacology

Mechanism of Action

Metabolism

Pharmacokinetics


Administration

PO Dosing

Effect on Anticoagulation Tests

Hepatic Dose Adjustment

Renal Dose Adjustment

Venous Thromboembolism

Non-Valvular Atrial Fibrillation

Deep Venous Thrombosis Prophylaxis After Hip/Knee Surgery

Dose Adjustment for Obesity (2016 International Society of Thrombosis and Hemostasis Recommendations) (J Thromb Haemost, 2016) [MEDLINE]

Conversion to/from Other Anticoagulants

Conversion from Apixaban

Conversion to Apixaban


Periprocedural/Perioperative Management of Apixaban Anticoagulation

Recommendations for Periprocedural/Perioperative Management of Apixaban (American College of Chest Physicians Clinical Practice Guideline for the Perioperative Management of Antithrombotic Therapy) (Chest, 2022) [MEDLINE]


Reversal of Apixaban Anticoagulation

Activated Charcoal (see Activated Charcoal)

Andexanet Alfa (see Andexanet)

Hemodialysis (see Hemodialysis)

Prothrombin Complex Concentrate-4 Factor (Kcentra, Beriplex, Confidex) (see Prothrombin Complex Concentrate-4 Factor)

Recombinant Factor VIIa (see Factor VIIa)


Adverse Effects

Hemorrhagic Adverse Effects

Comparative Rates of Hemorrhage Between Coumadin and Direct Oral Anticoagulants (DOAC’s)

Types of Hemorrhage

Other Adverse Effects


References

General

Indications

Atrial Fibrillation

Venous Thromboembolism

Administration

Use in Specific Clinical Subsets of Patients

Reversal of Anticoagulation

Adverse Effects