Apixaban (Eliquis)

Indications

Systemic Embolism Prevention in Nonvalvular Atrial Fibrillation (see Atrial Fibrillation, [[Atrial Fibrillation]])

  • FDA Approval: Dec, 2012 for non-valvular atrial fibrillation
  • AVERROES Trial (NEJM, 2011) [MEDLINE]: in patients with atrial fibrillation for whom vitamin K antagonist therapy was unsuitable, apixaban reduced the risk of stroke or 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)
    • Novel Oral Anticoagulants Decreased All-Cause Mortality, as Compared to Coumadin (risk ratio [RR], 0.88 [95% CI, 0.82 to 0.96]): novel oral anticoagulants are a viable option for patients receiving long-term anticoagulation, although the treatment benefits compared with warfarin are small and vary depending on the control achieved by coumadin treatment

Venous Thromboembolism-Deep Venous Thrombosis (DVT)/Acute Pulmonary Embolism (PE) (see Deep Venous Thrombosis, [[Deep Venous Thrombosis]] and Acute Pulmonary Embolism, [[Acute Pulmonary Embolism]])

  • FDA Approval: Aug, 2014 for venous thromboembolism
  • AMPLIFY-EXT Trial (Apixaban After the Initial Management of Pulmonary Embolism and Deep Venous Thrombosis with First-Line Therapy-Extended Treatment) (2012) [MEDLINE]
    • Study: funded by Bristol-Myers Squibb and Pfizer
      • RCT 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
        • Only 2% of patients had active cancer
    • Main Findings
      • Apixaban decreased all-cause death: 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 death from venous thromboembolism: 1.7% in apixaban groups vs 8.8% in placebo group
      • Apixaban decreased major bleeding: 0.2% in 2.5 mg group, 0.1% in 5 mg group, and 0.5% in placebo group
      • Apixaban increased clinically-relevant non-major bleeding: 3% in 2.5 mg group, 4.2% in 5 mg group, and 2.3% in placebo group
  • 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)
    • Novel Oral Anticoagulants Decreased All-Cause Mortality, as Compared to Coumadin (risk ratio [RR], 0.88 [95% CI, 0.82 to 0.96]): novel oral anticoagulants are a viable option for patients receiving long-term anticoagulation, although the treatment benefits compared with warfarin are small and vary depending on the control achieved by coumadin treatment
  • AMPLIFY Trial (Apixaban for Treatment of Acute Venous Thromboembolism) (2013) [MEDLINE]
    • Study: funded by Bristol-Myers Squibb and Pfizer
      • Randomized, double-blind study comparing apixaban (10 mg BID x7 days, followed by 5 mg BID x6 mo) with conventional therapy (subcutaneous enoxaparin, followed by warfarin)
      • n = 5395 patients with acute venous thromboembolism
    • Main Findings
      • Fixed-dose apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism
      • Apixaban was associated with significantly less bleeding than conventional therapy
        • Major bleeding occurred in 0.6% of patients who received apixaban and in 1.8% of those who received conventional therapy (relative risk, 0.31; 95% CI, 0.17 to 0.55; P<0.001 for superiority)
        • The composite outcome of major bleeding and clinically relevant nonmajor bleeding occurred in 4.3% of the patients in the apixaban group, as compared with 9.7% of those in the conven-tional-therapy group (relative risk, 0.44; 95% CI, 0.36 to 0.55; P<0.001)

Deep Venous Thrombosis (DVT) Prophylaxis in Medical Patients

  • Trial Examining Prolonged DVT Prophylaxis After Hospital Discharge in Medical Patients (2011) [MEDLINE]
    • Study: double-blind, double-dummy, placebo-controlled trial (n = 6528)
    • Main Findings: In medically ill patients, an extended course of DVT prophylaxis with apixaban was not superior to a shorter course with enoxaparin
      • Apixaban was associated with significantly more major bleeding events than enoxaparin

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

  • FDA Approval: Mar, 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]
    • Novel 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

  • Direct Factor Xa Inhibitor (see Factor Xa Inhibitors, [[Factor Xa Inhibitors]])
  • Metabolism
    • Compared to other new oral anticoagulants, apixaban metabolism appears to be the least sensitive to renal function
  • Half-Life: 12 hrs

Administration

PO Dosing

  • Non-Valvular Atrial Fibrillation: 5 mg BID
    • Decrease to 2.5 mg BID in patient age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL
  • Hip Replacement Deep Venous Thrombosis (DVT) Prophylaxis: 2.5 mg BID x 35 days
  • Knee Replacement Deep Venous Thrombosis (DVT) Prophylaxis: 2.5 mg BID x 12 days
  • Venous Thrombembolism: 10 mg BID x 10 days, then 5 mg BID
    • Note: rivaroxaban/apixaban do not require initial parenteral (heparin, etc) anticoagulation for the treatment of venous thromboembolism (see Rivaroxaban, [[Rivaroxaban]])
  • Reduction in Risk of Recurrent Venous Thrombomebolism: 2.5 mg BID after at least 6 mo of treatment for venous tromboembolism

Effect on Anticoagulation Tests

  • Prothrombin Time (PT)/International Normalized Ratio (INR) (see Prothrombin Time, [[Prothrombin Time]]): no effect-prolonged
  • Partial Thromboplastin Time (PTT) (see Partial Thromboplastin Time, [[Partial Thromboplastin Time]]): no effect-prolonged
  • Thrombin Time (TT) (see Thrombin Time, [[Thrombin Time]]): no effect
  • Anti-Factor Xa Activity (see Anti-Factor Xa Activity, [[Anti-Factor Xa Activity]]): no effect-prolonged
    • Effect depends on whether the specific laboratory’s activity assay is calibrated for the specific anticoagulant

Hepatic Dose Adjustment

  • Mild Liver Disease: none required
  • Severe Liver Disease: use of apixaban is not recommended

Renal Dose Adjustment

Venous Thromboembolism

  • Renal Insufficiency (US Package Labeling): no dose adjustment
    • However, patients with a Cr >2.5 mg/dL or CrCl <25 mL/min (by Cockcroft-Gault equation) were excluded from the clinical trials

Non-Valvular Atrial Fibrillation

  • Cr <1.5 mg/dL (US Package Labeling): no dose adjustment, except for the following
    • Age ≥80 y/o and Body Weight ≤60 kg: 2.5 mg PO BID
  • Cr ≥1.5 mg/dL and Either Age ≥80 y/o or Body Weight ≤60 kg (US Package Labeling): 2.5 mg PO BID
    • However, patients with a Cr >2.5 mg/dL or CrCl <25 mL/min (by Cockcroft-Gault equation) were excluded from the clinical trials
  • ESRD Requiring Hemodialysis (US Package Labeling): 5 mg BID
    • Age ≥80 y/o and Body Weight ≤60 kg: 2.5 mg PO BID

Deep Venous Thrombosis Prophylaxis After Hip/Knee Surgery

  • Renal Insufficiency (US Package Labeling): no dose adjustment
    • *However, patients with either clinically significant renal impairment (ADVANCE-1), impaired renal function (ADVANCE-2), or CrCl <30 mL/min (by Cockcroft-Gault equation) (ADVANCE-3) were excluded from the clinical trials

Conversion to/from Other Anticoagulants

Conversion from Apixaban

  • Conversion From Apixaban -> Unfractionated Heparin Drip/Low Molecular Weight Heparin (and Ultimately, Coumadin): discontinue apixaban and begin heparin drip/low molecular weight heparin at the time the next dose of apixaban would have been taken
    • Note: with just regard to eventual conversion to coumadin, apixaban affects the INR, so that initial INR measurements during the transition to coumadin may not be useful for determining the appropriate dose of coumadin
  • Conversion from Apixaban to Other Non-Coumadin Oral Anticoagulant: discontinue apixaban and begin taking the new non-coumadin anticoagulant at the usual time of the next scheduled dose of apixaban

Conversion to Apixaban

  • Conversion From Coumadin -> Apixaban: coumadin should be stopped and apixaban started when the INR is <2
  • Conversion from Non-Coumadin Anticoagulant to Apixaban: discontinue one being taken and begin the apixaban at the next scheduled dose

Management of Apixaban Anticoagulation for Procedures

  • Discontinue at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of bleeding

Reversal of Anticoagulation

  • Activated Charcoal (see Activated Charcoal, [[Activated Charcoal]])
    • Clinical Efficacy: indicated to decrease apixaban absorption
  • Andexanet (see Andexanet, [[Andexanet]])
    • Clinical Efficacy: investigational
  • Hemodialysis (see Hemodialysis, [[Hemodialysis]])
    • Clinical Efficacy: does not appear to impact apixaban clearance
  • Prothrombin Complex Concentrate-4 Factor (Kcentra, Beriplex, Confidex) (see Prothrombin Complex Concentrate-4 Factor, [[Prothrombin Complex Concentrate-4 Factor]])
    • Clinical Efficacy: suggested for apixaban-associated hemorrhage (Biomed Res Int, 2014) [MEDLINE]
    • Administration: 50 units/kg IV
  • Recombinant Factor VIIa (see Factor VIIa, [[Factor VIIa]])
    • Clinical Efficacy: may be considered if bleeding continues after prothrombin complex concentrate-4 factor (Kcentra, Beriplex, Confidex)

Adverse Effects

Hemorrhagic Adverse Effects

Comparative Rates of Hemorrhage Between Coumadin and Novel Oral Anticoagulants

  • 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)
    • Decreased Risk of Fatal Bleeding, as Compared to Coumadin (RR, 0.60 [CI, 0.46 to 0.77])
    • Decreased Risk of Major Bleeding, as Compared to Coumadin (RR, 0.80 [CI, 0.63 to 1.01])
    • Increased Risk of Gastrointestinal Bleeding, as Compared to Coumadin (RR, 1.30 [CI, 0.97 to 1.73])
    • Increased Risk of Discontinuation Due to Adverse Events, as Compared to Coumadin (RR, 1.23 [CI, 1.05 to 1.44])
    • Bleeding Risk for New Oral Anticoagulants May Be Higher in Patients >75 y/o or Those Receiving Coumadin Who Have Good Control
  • Systematic Review/Meta-Analysis Comparing Rates of Hemorrhage of Novel Oral Anticoagulants vs Coumadin When Used in the Setting of Renal Insufficiency (Chest, 2016) [MEDLINE]
    • CrCl 50-80 mL/min: novel oral anticoagulants had a significantly decreased risk of major bleeding, as compared to coumadin
    • CrCl <50 mL/min: novel oral anticoagulants had a non-significantly decreased risk of major bleeding, as compared to coumadin
      • Apixaban had the lowest rate of major bleeding in this subgroup

Types of Hemorrhage

Other Adverse Effects

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References

  • Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokin 2009;48(1):1-22 [MEDLINE]
  • AVERROES Trial: Apixaban in patients with atrial fibrillation. N Engl J Med. 2011 Mar 3;364(9):806-17. doi: 10.1056/NEJMoa1007432. Epub 2011 Feb 10 [MEDLINE]
  • Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med. 2011 Dec 8;365(23):2167-77. doi: 10.1056/NEJMoa1110899. Epub 2011 Nov 13 [MEDLINE]
  • Apixaban for Extended Treatment of Venous Thromboembolism (AMPLIFY-EXT). December 8, 2012 DOI: 10.1056/NEJMoa1207541 [MEDLINE]
  • Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism: a systematic review. Ann Intern Med. 2012 Dec 4;157(11):796-807 [MEDLINE]
  • Systematic review of randomized controlled trials of new anticoagulants for venous thromboembolism prophylaxis in major orthopedic surgeries, compared with enoxaparin. Ann Vasc Surg. 2013 Apr;27(3):355-69. doi: 10.1016/j.avsg.2012.06.010. Epub 2013 Jan 23 [MEDLINE]
  • New oral anticoagulants in the treatment of pulmonary embolism: efficacy, bleeding risk, and monitoring. Thrombosis 2013;2013:973710. doi: 10.1155/2013/973710 [MEDLINE]
  • Oral apixaban for the treatment of acute venous thromboembolism (AMPLIFY). N Engl J Med. 2013 Aug 29;369(9):799-808. doi: 10.1056/NEJMoa1302507. Epub 2013 Jul 1 [MEDLINE]

  • Management of the bleeding patient receiving new oral anticoagulants: a role for prothrombin complex concentrates. BioMed Res Int. 2014; Article ID 583794 [MEDLINE]

  • Treatment of intracerebral hemorrhage associated with new oral anticoagulant use: the neurologist’s view. Clin Lab Med. 2014;34:587–594 [MEDLINE]

  • Reversal of anticoagulants: an overview of current developments. Thromb Haemost. 2015;113(5):931–942 [MEDLINE]

  • Major Bleeding and Hemorrhagic Stroke with Direct Oral Anticoagulants in Patients with Renal Failure: Systematic Review and Meta-Analysis of Randomized Trials. Chest. 2016,(): doi:10.1016/j.chest.2015.12.029 [MEDLINE]