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)

Mechanism of Action

• Direct Factor Xa Inhibitor (see Factor Xa Inhibitors)

Metabolism

• Hepatic predominantly via CYP3A4/5 and to a lesser extent via CYP1A2, 2C8, 2C9, 2C19, and 2J2 to inactive metabolites; O-demethylation and hydroxylation are the major sites of transformation; substrate of P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP)
• Excretion: Urine (~27% as parent drug); feces (biliary and direct intestinal excretion
• Compared to Other Oral Anticoagulants, Apixaban Metabolism Appears to Be the Least Sensitive to Renal Function

Pharmacokinetics

• Onset of Action 3-4 hrs
• Peak Onset of Action: 3-4 hrs
• Half-Life: 12 hrs (Range: 8-15 hrs)

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)
• 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): no effect-prolonged
• Partial Thromboplastin Time (PTT) (see Partial Thromboplastin Time): no effect-prolonged
• Thrombin Time (TT) (see Thrombin Time): no effect
• Anti-Factor Xa Activity (see 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 (in ADVANCE-1), Impaired Renal Function (in ADVANCE-2), or CrCl <30 mL/min (by Cockcroft-Gault equation) (ADVANCE-3) were Excluded from the Clinical Trials

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

• BMI ≤40 kg/m2 and Weight <120 kg: standard dosing is recommended for both venous thromboembolism and atrial fibrillation
• BMI >40 kg/m2 or Weight >120 kg: direct oral anticoagulants are not recommended (due to limited clinical data and possibility that patient may be underdosed)
  • If Direct Oral Anticoagulants are Used in this Patient Group, Drug-Specific Peak and Trough Levels (Anti-Factor Xa for Apixaban/Edoxaban/Rivaroxaban, Ecarin Time or Dilute Thrombin Time with Appropriate Calibrators for Dabigatran, or Mass Spectrometry for Any of the Agents) Should Be Measured: if levels fall below the expected range, change to coumadin is recommended (rather than dose adjustment of the direct oral anticoagulant)

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

Activated Charcoal (see Activated Charcoal)

• Clinical Efficacy: indicated to decrease apixaban absorption

Andexanet Alfa (see Andexanet)

• Pharmacology
  • Andexanet Alfa is a Modified Recombinant Derivative of Factor Xa Which Acts as a Decoy Receptor
    • Andexanet Alfa Has a Higher Affinity for the Factor Xa Inhibitor Drug than Natural Factor Xa
    • Consequently Drug Binds to Andexanet Alfa, Rather than Factor Xa Itself
• Clinical Efficacy
  • ANNEXA-4 Trial of Andexanet Alfa for the Treatment of Major Hemorrhage Associated with Factor Xa Inhibitors (NEJM, 2016) [MEDLINE]
    • Andexanet Alfa (Initial Bolus and Subsequent Infusion x 2 hrs) Decreased Factor Xa Activity in Patients with Major Hemorrhage Associated with Factor Xa Inhibitors: effective hemostasis occurred in 79% of patients
      • After the Bolus (and Remaining Approximately the Same During the Infusion), Anti-Factor Xa Activity was Decreased 93% from Baseline in Patients on Apixaban
      • After the Bolus (and Remaining Approximately the Same During the Infusion), Anti-Factor Xa Activity was Decreased 89% from Baseline in Patients on Rivaroxaban
      • Thrombotic Events Occurred in 18% of Patients within 30 Days

Hemodialysis (see Hemodialysis)

• Clinical Efficacy: does not appear to impact apixaban clearance

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

• Clinical Efficacy: may be considered if bleeding continues after prothrombin complex concentrate-4 factor (Kcentra, Beriplex, Confidex)

Hemorrhagic Adverse Effects

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

• 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: direct oral anticoagulants had a significantly decreased risk of major bleeding, as compared to coumadin
  • CrCl <50 mL/min: direct 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

• Adrenal Hemorrhage (see Adrenal Insufficiency)
• Diffuse Alveolar Hemorrhage (DAH) (see Diffuse Alveolar Hemorrhage)
• Epistaxis (see Epistaxis)
• Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage)
• Hematuria (see Hematuria)
• Intracerebral Hemorrhage (Hemorrhagic Cerebrovascular Accident) (see Intracerebral Hemorrhage)
• Intracranial Epidural Hematoma (see Intracranial Epidural Hematoma)
• Retroperitoneal Hemorrhage (see Retroperitoneal Hemorrhage)
• Spinal Epidural Hematoma (see Spinal Epidural Hematoma)
• Subarachnoid Hemorrhage (SAH) (see Subarachnoid Hemorrhage)
• Subdural Hematoma (SDH) (see Subdural Hematoma)

Other Adverse Effects

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