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Eliquis

Generic Name: Apixaban
Class: Direct Factor Xa Inhibitors
Chemical Name: 1H - Pyrazolo[3,4 - c]pyridine - 3 - carboxamide,4,5,6,7 - tetrahydro - 1 - (4 - methoxyphenyl) - 7 - oxo - 6 - [4 - (2 - oxo - 1 - piperidinyl)phenyl]
Molecular Formula: C25H25N5O4
CAS Number: 503612-47-3

Warning(s)

  • Increased Risk of Stroke Following Discontinuance of Therapy
  • Increased risk of thrombotic events (e.g., stroke) following discontinuance of apixaban therapy in patients with nonvalvular atrial fibrillation.1

  • If discontinuance is required for reasons other than for pathologic bleeding (e.g., prior to surgery to minimize bleeding risk), strongly consider coverage with an alternative anticoagulant.1 (See Risk of Stroke Following Discontinuance of Therapy under Cautions.)

REMS:

FDA approved a REMS for apixaban to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of apixaban and consists of the following: communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Anticoagulant; an oral, reversible, direct activated factor X (factor Xa) inhibitor.1 3 5 8 9 28 31 32 33 35 39 42

Uses for Eliquis

Embolism Associated with Atrial Fibrillation

Reduction in the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.1 3 5 8 40 42 1007

More effective than warfarin in reducing the risk of stroke and systemic embolism, major bleeding, and all-cause mortality in such patients.1 3 24

The American College of Chest Physicians (ACCP), American Stroke Association (ASA), ACC, AHA, and other experts recommend antithrombotic therapy (e.g., warfarin, aspirin) in all patients with paroxysmal (intermittent) or permanent atrial fibrillation, unless contraindicated.989 990 999 1007

Choice of antithrombotic therapy is based on patient's level of risk for stroke; in general, oral anticoagulant therapy (traditionally warfarin) is recommended in patients with moderate to high risk for stroke, while aspirin is recommended in low-risk patients and those with contraindications to oral anticoagulant therapy.7 988 989 990 999 1007 Patients considered to be at increased risk of stroke generally include those with prior ischemic stroke or TIA, advanced age (e.g., ≥75 years), history of hypertension, diabetes mellitus, or recent exacerbation of CHF.7 990 999 1007

Apixaban is recommended by some experts as a useful alternative to warfarin in patients at moderate to high risk of stroke who are unable to comply with warfarin monitoring requirements or in whom a consistent therapeutic response to warfarin cannot be achieved; warfarin may still be preferred in patients who have well-controlled INRs and are compliant with regular laboratory monitoring.10 12 25 70 71 73

Slideshow: 2013 Drug News Round-Up: Top 20 Stories

Relative efficacy and safety of apixaban and other newer oral anticoagulants (e.g., dabigatran, rivaroxaban) remains to be fully elucidated.9 10 29 66 67 68 70 989

When selecting an appropriate anticoagulant, consider factors such as individual patient's risks of stroke and bleeding; patient compliance, preference, and comorbidities; cost; and availability of agents to reverse anticoagulant effects in case of bleeding complications.8 72 988 989 999 1007

Not recommended in patients with prosthetic heart valves.1

Thromboprophylaxis in Hip- or Knee-Replacement Surgery

Has been used for the prevention of postoperative DVT and PE in patients undergoing total hip- or knee-replacement surgery8 9 31 32 33 34 35 36 37 38 39 40 42 1003

More effective than sub-Q enoxaparin sodium 40 mg once daily in reducing risk of venous thromboembolism with similar rates of bleeding.32 33 Noninferiority of apixaban (2.5 mg twice daily) and currently recommended US dosing regimen for sub-Q enoxaparin sodium in knee-replacement surgery (30 mg twice daily)47 not established.31

ACCP and other clinicians consider apixaban an acceptable option for pharmacologic thromboprophylaxis in patients undergoing total hip- or knee-replacement surgery;35 38 39 74 1003 however, a low molecular weight heparin (LMWH) generally is preferred.1003 Apixaban may be a reasonable choice when an LMWH is not available or cannot be used.1003

Data currently lacking on efficacy and safety of apixaban thromboprophylaxis in patients undergoing hip-fracture surgery.74 1003

When selecting an appropriate thromboprophylaxis regimen, consider factors such as relative efficacy, bleeding risk, logistics, and compliance.1003

Treatment and Secondary Prevention of Venous Thromboembolism

Has been used successfully for acute treatment43 44 48 and secondary prevention (extended treatment)45 46 of DVT and/or PE.43 44 45 46

For acute treatment of symptomatic venous thromboembolism, efficacy appears similar to conventional anticoagulant therapy (sub-Q enoxaparin followed by warfarin therapy adjusted to INR of 2–3 for 6 months) with lower incidence of major bleeding.43 44

For secondary prevention following 6–12 months of initial anticoagulant therapy (e.g., with apixaban or enoxaparin and warfarin therapy), extended therapy with apixaban reduced incidence of symptomatic recurrent venous thromboembolism without increasing rate of major bleeding.45 46

Limited data on efficacy and safety in patients with cancer, low body weight (<60 kg), or renal insufficiency (Clcr <50 mL/minute); additional study required.43 44 45 46

Thromboprophylaxis in Acute Medical Illness

Current evidence in patients with acute medical illness suggests that extended treatment with apixaban (2.5 mg twice daily for 30 days) is not superior to short-term sub-Q enoxaparin sodium (40 mg once daily for 6–14 days) and is associated with an increased risk of major bleeding.51

Acute Coronary Syndrome

Current evidence suggests that addition of apixaban to standard antiplatelet therapy (e.g., aspirin, clopidogrel) in patients with acute coronary syndrome (ACS) is associated with an increased risk of major (sometimes fatal) bleeding without substantial reduction in recurrent ischemic events.49 50 75

Eliquis Dosage and Administration

General

  • Routine monitoring of coagulation tests not required.8 19 22 30 40 989

  • Coagulation tests such as aPTT, PT, INR, and the Heptest (used to measure inhibition of exogenous factor Xa) generally not useful because of variable and inconsistent results.1 8 19 28 40 42

  • A chromogenic anti-factor Xa assay (Rotachrom Heparin chromogenic assay) has been used to measure factor Xa activity;1 however, not recommended by manufacturer for assessing anticoagulant effects of apixaban.1

Administration

Oral Administration

Administer orally twice daily with or without food.1

If a dose is missed, take as soon as possible on the same day, then resume regular schedule; do not double dose to compensate for a missed dose.1

Dosage

Adults

Embolism Associated with Atrial Fibrillation
Oral

5 mg twice daily.1

Reduce dosage to 2.5 mg twice daily in patients with at least 2 of the following characteristics: age ≥80 years, body weight ≤60 kg, Scr ≥1.5 mg/dL.1 42 (See Special Populations under Dosage and Administration.)

Reduce dosage to 2.5 mg twice daily in patients receiving concomitant therapy with drugs that are potent inhibitors of both CYP3A4 and P-glycoprotein (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin); avoid use of such potent dual inhibitors of CYP3A4 and P-glycoprotein in patients who are already receiving apixaban 2.5 mg twice daily.1 (See Drugs Affecting P-glycoprotein and CYP3A4 under Interactions.)

Transitioning to Apixaban from Warfarin
Oral

Discontinue warfarin and initiate apixaban as soon as INR <2.1

Transitioning to Warfarin from Apixaban
Oral

INR measurements may not be useful in determining appropriate dosage of warfarin because apixaban can also prolong INR.1 If continuous anticoagulation is necessary, may discontinue apixaban and simultaneously initiate a parenteral anticoagulant and warfarin at the time of the next scheduled dose of apixaban; discontinue parenteral anticoagulant once acceptable INR achieved.1

Other strategies for transitioning from apixaban to warfarin based on patient’s Clcr and warfarin start date suggested.78

Transitioning to and from Therapy with Anticoagulants Other than Warfarin
Oral

Discontinue anticoagulant currently being taken, and initiate the other at the time of the next scheduled dose.1 14

Thromboprophylaxis in Hip- or Knee-Replacement Surgery
Oral

2.5 mg twice daily.1

In clinical studies, initial dose was administered 12–24 hours after wound closure; treatment was continued postoperatively for 10–14 days after knee-replacement surgery and for 32–38 days after hip-replacement surgery.31 32 33

Treatment and Secondary Prevention of Venous Thromboembolism
Oral

Acute treatment: 10 mg twice daily for 7 days, then 5 mg twice daily for 6 months.43 44

Extended treatment (secondary prevention after 6–12 months of initial anticoagulant therapy): 2.5 or 5 mg twice daily; both dosages appear to have similar efficacy and safety.45 46

Managing Anticoagulation in Patients Requiring Invasive Procedures

Temporarily interrupt apixaban therapy prior to elective surgery or other invasive procedure.1 18 68 For procedures associated with a moderate to high risk of unacceptable or clinically important bleeding, discontinue ≥48 hours prior to the procedure.1 For procedures associated with a low risk of bleeding or bleeding in a noncritical location that can be easily controlled, discontinue ≥24 hours prior to the procedure.1

Resume therapy after procedure when considered safe to do so; although experience limited, some experts suggest that timing of resumption be based on procedural bleeding risk and hemostasis.18 68 74 76

Special Populations

Hepatic Impairment

No dosage adjustment necessary in patients with mild hepatic impairment.1 Because of limited experience, manufacturer states dosage recommendations cannot be provided in patients with moderate hepatic impairment.1 77 Use not recommended in patients with severe hepatic impairment.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Manufacturer states that dosage adjustment based solely on renal function not necessary.1 77 Reduce dosage to 2.5 mg twice daily in patients with Scr ≥1.5 mg/dL if they have at least one of the following additional characteristics: age ≥80 years or body weight ≤60 kg.1 (See Renal Impairment under Cautions.)

Geriatric Patients

Manufacturer states that dosage adjustment based solely on age not necessary.1 Reduce dosage to 2.5 mg twice daily in geriatric patients ≥80 years of age if they have at least one of the following additional characteristics: Scr ≥1.5 mg/dL or body weight ≤60 kg.1

Body Weight

Manufacturer states that dosage adjustment based solely on body weight not necessary.1 Reduce dosage to 2.5 mg twice daily in patients who weigh ≤60 kg if they have at least one of the following additional characteristics: age ≥80 years or Scr ≥1.5 mg/dL.1

Race/Ethnicity

No dosage adjustment necessary.1

Cautions for Eliquis

Contraindications

  • Active pathologic bleeding.1

  • Severe hypersensitivity reaction to apixaban.1

Warnings/Precautions

Warnings

Risk of Stroke Following Discontinuance of Therapy

Increased risk of thromboembolic events if apixaban discontinued in the absence of adequate alternative anticoagulation in patients with nonvalvular atrial fibrillation.1 9 74 (See Boxed Warning.) An increased risk of stroke was observed during transition from apixaban to warfarin therapy in clinical trials of such patients.1 9

If discontinuance is required for reasons other than for pathologic bleeding, strongly consider coverage with an alternative anticoagulant.1 (See Managing Anticoagulation in Patients Requiring Invasive Procedures under Dosage and Administration.)

Advise patients regarding importance of adhering to therapeutic regimen and on steps to take if doses are missed.1 (See Advice to Patients.)

Other Warnings and Precautions

Bleeding

Increases risk of hemorrhage and can cause serious, sometimes fatal, bleeding.1 3 5 18 19 21 Discontinue if active pathologic hemorrhage occurs.1 (See Contraindications under Cautions.)

Renal impairment or concomitant use of drugs that affect hemostasis (e.g., aspirin or other antiplatelet drugs, NSAIAs, fibrinolytics, heparin or other anticoagulants, SSRIs, SNRIs) or drugs that inhibit both P-glycoprotein and CYP3A4 may increase risk of bleeding.1 6 42 (See Interactions.)

Temporarily interrupt therapy prior to any elective surgery or other invasive procedure to reduce risk of bleeding.1 9 (See Managing Anticoagulation in Patients Requiring Invasive Procedures under Dosage and Administration.)

No specific antidote or reversal agent.1 4 9 19 If serious bleeding occurs, discontinue drug and initiate appropriate treatment.1 13 22 989 Not expected to be dialyzable because of high plasma protein binding.1 May consider use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), anti-inhibitor coagulant complex (activated prothrombin complex concentrate), or factor VIIa (recombinant); however, efficacy not established in clinical studies.1 9 13 19 Protamine sulfate and vitamin K not expected to affect anticoagulant activity of apixaban, and no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) or systemic hemostatics (desmopressin, aprotinin).1 If overdosage occurs, may consider use of activated charcoal to decrease plasma apixaban concentrations more rapidly.1 19

Patients with Prosthetic Heart Valves

Safety and efficacy not established in patients with prosthetic heart valves; use not recommended in such patients.1 9

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., skin rash, allergic edema, anaphylactic reactions) reported.1 (See Contraindications under Cautions.)

Specific Populations

Pregnancy

Category B.1

No adequate data in pregnant women; increased maternal bleeding observed in animals.1

Because apixaban is likely to increase risk of bleeding during pregnancy and delivery, use only when benefits justify risks.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in patients <18 years of age.1 3 4 9

Geriatric Use

No substantial differences in efficacy and safety relative to younger adults.1

Hepatic Impairment

Pharmacokinetics and pharmacodynamics (inhibition of factor Xa activity) not substantially altered in patients with mild or moderate hepatic impairment.1 (See Special Populations under Pharmacokinetics.) Patients with moderate hepatic impairment may have intrinsic coagulation abnormalities that can affect response to therapy; however, impact of this effect not clear.1 77

Data lacking in patients with severe hepatic impairment; manufacturer recommends against use in such patients.1

Renal Impairment

Pharmacokinetics and pharmacodynamic effects not substantially altered in patients with renal impairment.1 (See Special Populations under Pharmacokinetics.)

Race/Ethnicity

Pharmacokinetics were similar among patients of different ethnic origins (Caucasian, Asian, and African-American).1 8 42 (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Bleeding.1 3 5

Interactions for Eliquis

Metabolized by CYP3A4/5, and to a lesser extent by CYP isoenzymes 1A2, 2C8, 2C9, 2C19, and 2J2.1 15

Does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 3A4/5, or 2C19 nor induce CYP isoenzymes 1A2, 2B6, or 3A4/5.1 15 16

Substrate of the efflux transporter P-glycoprotein, but does not substantially inhibit P-glycoprotein.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP3A4/5: Although pharmacokinetic interactions are possible, potential may be low because of apixaban’s multiple routes of elimination.8 15 35 77

Pharmacokinetic interactions unlikely with drugs metabolized by major CYP isoenzymes.1 15 16

Drugs Affecting P-glycoprotein Transport

Inhibitors or inducers of P-glycoprotein: Potential pharmacokinetic interaction.1

Drugs Affecting P-glycoprotein and CYP3A4

Combined P-glycoprotein and CYP3A4 inhibitors: Possible increased apixaban exposure, which may increase risk of bleeding.1 Reduce dosage if used concomitantly with a potent dual inhibitor of P-glycoprotein and CYP3A4; avoid use if patient already receiving reduced dosage.1 (See Dosage under Dosage and Administration and also see Specific Drugs under Interactions.)

Combined P-glycoprotein and CYP3A4 inducers: Possible decreased apixaban exposure, which may increase risk of stroke.1 Avoid concomitant use with potent dual inducers of P-glycoprotein and CYP3A4.1

Drugs Affecting Hemostasis

Potential increased risk of hemorrhage.1 8 Promptly evaluate any manifestations of bleeding.1

Specific Drugs

Drug

Interaction

Comments

Amiodarone

Efficacy and safety of apixaban not altered with concomitant use9

Antifungals, azole (i.e., itraconazole, ketoconazole)

Possible increased exposure to apixaban and risk of bleeding; result of dual CYP3A4 and P-glycoprotein inhibiting effect by itraconazole or ketoconazole 1

Reduce apixaban dosage to 2.5 mg twice daily; avoid concomitant use if patient already receiving reduced dosage1

Avoid concomitant use of ketoconazole and apixaban in patients with at least 2 of the following characteristics: age ≥80 years, body weight ≤60 kg, Scr ≥1.5 mg/dL1

Aspirin

Increased bleeding risk observed1

Pharmacokinetics of aspirin not substantially altered in healthy individuals1

Atenolol

Pharmacokinetics of atenolol or apixaban not substantially altered in healthy individuals1

Carbamazepine

Possible decreased exposure to apixaban and increased risk of stroke; result of dual CYP3A4 and P-glycoprotein inducing effect by carbamazepine1

Avoid concomitant use1

Clarithromycin

Possible increased exposure to apixaban and risk of bleeding; result of dual CYP3A4 and P-glycoprotein inhibiting effect by clarithromycin1

Reduce apixaban dosage to 2.5 mg twice daily; avoid concomitant use if patient already receiving reduced dosage1

Clopidogrel

Pharmacodynamic interaction not observed1

Increased risk of bleeding observed in patients receiving apixaban in combination with aspirin and clopidogrel1 50

Digoxin

Pharmacokinetics of digoxin not substantially altered in healthy individuals1

Diltiazem

Moderate increase in systemic exposure and peak plasma concentrations of apixaban1

No dosage adjustment necessary1

Enoxaparin

No effect on pharmacokinetics of apixaban; additive effect on peak anti-factor Xa activity but considered to be modest1 14

Famotidine

Pharmacokinetics of apixaban not substantially altered in healthy individuals1

Fibrinolytics

Potential increased risk of hemorrhage1

Heparin

Potential increased risk of hemorrhage1

NSAIAs (e.g., naproxen)

Potential increased risk of hemorrhage with chronic use1

Naproxen: Pharmacokinetics of naproxen not substantially altered in healthy individuals, but systemic exposure and peak plasma concentrations of apixaban were moderately increased; anti-factor Xa activity increased by about 50–60%1

No dosage adjustment necessary when used concomitantly with naproxen1

Phenytoin

Possible decreased exposure to apixaban and increased risk of stroke; result of dual CYP3A4 and P-glycoprotein inducing effect by phenytoin1

Avoid concomitant use1

Rifampin

Substantially decreased exposure and peak plasma concentrations of apixaban, which may increase risk of stroke; result of dual CYP3A4 and P-glycoprotein inducing effect by rifampin 1

Avoid concomitant use1

Ritonavir

Possible increased exposure to apixaban and risk of bleeding; result of dual CYP3A4 and P-glycoprotein inhibiting effect by ritonavir1

Reduce apixaban dosage to 2.5 mg twice daily; avoid concomitant use if patient already receiving reduced dosage1

SNRIs

Possible increased risk of hemorrhage1

SSRIs

Possible increased risk of hemorrhage1

St. John's wort (Hypericum perforatum)

Possible decreased exposure to apixaban and increased risk of stroke; result of dual CYP3A4 and P-glycoprotein inducing effect by St. John's wort1

Avoid concomitant use1

Eliquis Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability approximately 50%.1 17 28

Following oral administration, peak plasma concentrations occur within approximately 3–4 hours.1 17 28

Absorption occurs throughout GI tract; about 55% of dose absorbed in distal small intestine and ascending colon.1

Food

Food does not appear to affect systemic exposure or peak plasma concentrations.1 17

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

Approximately 87%.1 28

Elimination

Metabolism

Metabolized principally by CYP3A4/5 with minor contributions from CYP isoenzymes 1A2, 2C8, 2C9, and 2J2.1 15 No active circulating metabolites.1

Elimination Route

Eliminated via multiple pathways, including hepatic metabolism and intestinal, biliary, and renal excretion; approximately 25% of an administered dose is eliminated renally.1 15 16 42 77

Not expected to be removed by dialysis due to high plasma protein binding.1

Half-life

Clearance half-life approximately 6 hours, but apparent half-life longer (approximately 12 hours) following repeated administration because of prolonged absorption.1 17

Special Populations

Systemic exposure and peak plasma concentrations not substantially altered in patients with mild or moderate hepatic impairment.1

Systemic exposure and peak plasma concentrations not substantially altered in patients with mild, moderate, or severe renal impairment.1

Systemic exposure and peak plasma concentrations are similar in patients ≥65 years of age and younger adults (18–40 years of age).1

Peak plasma concentrations, half-life, and time to steady-state are similar among patients of different ethnic origins (e.g., Caucasian, Asian, African-American).1 8 42

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Actions

  • Binds selectively and with high affinity to active site of factor Xa; inhibits free and clot-bound factor Xa and prothrombinase activity.1 38 42

  • Inhibition of coagulation factor Xa prevents conversion of prothrombin to thrombin and subsequent thrombus formation.1 28 42

  • Unlike fondaparinux, heparin, and LMWHs, apixaban blocks factor Xa directly and does not require a cofactor (antithrombin III) to exert its anticoagulant activity.1 38 42

  • Inhibits factor Xa activity and prolongs PT, aPTT, and HepTest (an indirect measure of factor Xa activity) in a concentration-dependent manner.1 8 28

Advice to Patients

  • Importance of taking the drug exactly as prescribed and not discontinuing therapy without first consulting a clinician.1 2

  • Importance of advising patients that if a dose is missed, to take it as soon as possible on the same day and then resume the regular twice-daily dosing schedule; the missed dose should not be doubled.1 2

  • Importance of informing patients that they may bruise and/or bleed more easily and that a longer than normal time may be required to stop bleeding when taking apixaban; clinicians should advise patients on how to recognize signs and symptoms of bleeding.1 2 Importance of patients informing clinicians immediately about any unusual bleeding or bruising during therapy.1 2

  • Importance of patients informing clinicians (e.g., physicians, dentists) that they are receiving apixaban therapy before scheduling any surgery or invasive procedures, including dental procedures.1 2

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2

  • Importance of informing clinicians (e.g., physicians, dentists) of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements.1 2

  • Importance of informing patients of other important precautionary information.1 2 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Apixaban

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

2.5 mg

Eliquis

Bristol-Myers Squibb

5 mg

Eliquis

Bristol-Myers Squibb

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 2, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Bristol-Myers Squibb. Eliquis (apixaban ) oral tablets prescribing information. Princeton, NJ: 2012 Dec.

2. Bristol-Myers Squibb. Eliquis (apixaban) tablets medication guide. Princeton, NJ; 2012 Dec.

3. Granger CB, Alexander JH, McMurray JJ et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011; 365:981-92. [PubMed 21870978]

4. Lopes RD, Alexander JH, Al-Khatib SM et al. Apixaban for reduction in stroke and other ThromboemboLic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. Am Heart J. 2010; 159:331-9. [PubMed 20211292]

5. Connolly SJ, Eikelboom J, Joyner C et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011; 364:806-17. [PubMed 21309657]

6. Hohnloser SH, Hijazi Z, Thomas L et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J. 2012; 33:2821-30. [PubMed 22933567]

7. Lopes RD, Al-Khatib SM, Wallentin L et al. Efficacy and safety of apixaban compared with warfarin according to patient risk of stroke and of bleeding in atrial fibrillation: a secondary analysis of a randomised controlled trial. Lancet. 2012; 380:1749-58. [PubMed 23036896]

8. Nutescu E, Rhoades R, Bailey C et al. Apixaban: a novel oral inhibitor of factor Xa. Am J Health Syst Pharm. 2012; 69:1113-26. [PubMed 22722590]

9. Bristol-Myers Squibb, Princeton, NJ: Personal communication.

10. Mega JL. A new era for anticoagulation in atrial fibrillation. N Engl J Med. 2011; 365:1052-4. [PubMed 21870977]

11. Wallentin L, Lopes RD, Alexander J et al. Efficacy and safety of apixaban compared with warfarin at different levels of INR control for stroke prevention in atrial fibrillation. European Society of Cardiology, Update in Clinical Trial Session, Paris, 2011.

12. Vassiliou VS, Flynn PD. Apixaban in atrial fibrillation: does predicted risk matter?. Lancet. 2012; 380:1718-20. [PubMed 23036897]

13. Vassiliou VS. Apixaban versus warfarin in atrial fibrillation. N Engl J Med. 2012; 366:88; author reply 89. [PubMed 22216849]

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15. Wang L, Zhang D, Raghavan N et al. In vitro assessment of metabolic drug-drug interaction potential of apixaban through cytochrome P450 phenotyping, inhibition, and induction studies. Drug Metab Dispos. 2010; 38:448-58. [PubMed 19940026]

16. Raghavan N, Frost CE, Yu Z et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos. 2009; 37:74-81. [PubMed 18832478]

17. Frost C, Wang J, Nepal S et al. Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects. Br J Clin Pharmacol. 2013; 75:476-87. [PubMed 22759198]

18. Sié P, Samama CM, Godier A et al. Surgery and invasive procedures in patients on long-term treatment with direct oral anticoagulants: thrombin or factor-Xa inhibitors. Recommendations of the Working Group on Perioperative Haemostasis and the French Study Group on Thrombosis and Haemostasis. Arch Cardiovasc Dis. 2011; 104:669-76. [PubMed 22152517]

19. Miyares MA, Davis K. Newer oral anticoagulants: a review of laboratory monitoring options and reversal agents in the hemorrhagic patient. Am J Health Syst Pharm. 2012; 69:1473-84. [PubMed 22899742]

20. . Apixaban strengthens its case in atrial fibrillation. BMJ. 2012; 345:e6731.

21. Flaker GC, Eikelboom JW, Shestakovska O et al. Bleeding during treatment with aspirin versus apixaban in patients with atrial fibrillation unsuitable for warfarin: the apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment (AVERROES) trial. Stroke. 2012; 43:3291-7. [PubMed 23033347]

22. . Should direct thrombin inhibitors replace warfarin for prophylaxis of thromboembolism in canadians with atrial fibrillation?. Can J Hosp Pharm. 2012; 65:401-5. [PubMed 23129871]

23. Eikelboom JW, Connolly SJ, Gao P et al. Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease. J Stroke Cerebrovasc Dis. 2012; 21:429-35. [PubMed 22818021]

24. Easton JD, Lopes RD, Bahit MC et al. Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial. Lancet Neurol. 2012; 11:503-11. [PubMed 22572202]

25. Nedeltchev K. Critique of apixaban versus warfarin in patients with atrial fibrillation. Stroke. 2012; 43:922-3. [PubMed 22308243]

26. Diener HC, Eikelboom J, Connolly SJ et al. Apixaban versus aspirin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a predefined subgroup analysis from AVERROES, a randomised trial. Lancet Neurol. 2012; 11:225-31. [PubMed 22305462]

27. Cannon CP, Kohli P. Danger ahead: watch out for indirect comparisons!. J Am Coll Cardiol. 2012; 60:747-8. [PubMed 22898071]

28. He K, Luettgen JM, Zhang D et al. Preclinical pharmacokinetics and pharmacodynamics of apixaban, a potent and selective factor Xa inhibitor. Eur J Drug Metab Pharmacokinet. 2011; 36:129-39. [PubMed 21461793]

29. Giorgi MA, Cohen Arazi H, Gonzalez CD et al. Changing anticoagulant paradigms for atrial fibrillation: dabigatran, apixaban and rivaroxaban. Expert Opin Pharmacother. 2011; 12:567-77. [PubMed 21254865]

30. Eikelboom JW, O'Donnell M, Yusuf S et al. Rationale and design of AVERROES: apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment. Am Heart J. 2010; 159:348-353.e1. [PubMed 20211294]

31. Lassen MR, Raskob GE, Gallus A et al. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009; 361:594-604. [PubMed 19657123]

32. Lassen MR, Raskob GE, Gallus A et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010; 375:807-15. [PubMed 20206776]

33. Lassen MR, Gallus A, Raskob GE et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010; 363:2487-98. [PubMed 21175312]

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