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Dec.04.2015

Oral Anticoagulants

Summary

  • Novel oral anticoagulants (NOACs) include direct thrombin inhibitors (e.g., dabigatran) and factor Xa inhibitors (e.g., apixaban, betrixaban, edoxaban, and rivaroxaban).
  • Warfarin has a slower onset of action and longer half-life compared to the NOACs.
  • Routine laboratory monitoring is required with warfarin therapy, but not generally needed with NOACs.
  • Warfarin therapy is complicated by unpredictable pharmacokinetics, large interpatient variability, and large number of drug-drug and drug-food interactions.
  • A lower incidence of major, adverse bleeding events has been found in clinical trials of the NOACs as compared to warfarin.
  • Anticoagulation reversal agents are available for apixaban, dabigatran, rivaroxaban, and warfarin, but not for betrixaban or edoxaban.

Pharmacology/Mechanism of Action

Direct Thrombin Inhibitors

  • Dabigatran etexilate meslyate is absorbed as dabigatran etexilate ester, which then undergoes hydrolysis to form the active moiety, dabigatran.
  • Dabigatran competitively and reversibly inhibits both free and clot-bound thrombin (factor IIa), which blocks the conversion of soluble fibrinogen to insoluble fibrin and prevents the activation of factors V, VIII, XI and XIII that are involved in thrombin production and clot stabilization.
  • Dabigatran has dose-proportional pharmacokinetics.
  • It is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) system, but is a substrate of the efflux transporter P-glycoprotein (P-gp).
  • Primary route of elimination is renal; thus, dose adjustments are needed in renal impairment.[60374][60375][60376][60377][60378]

 

Factor Xa Inhibitors

  • Apixaban, betrixaban, edoxaban, and rivaroxaban are direct, selective inhibitors of free, clot-bound and prothrombinase complex-bound factor Xa. Factor Xa catalyzes the conversion of prothrombin to thrombin. Thrombin activates the conversion of fibrinogen to fibrin, which aids in clot formation and stabilization. Thus, factor Xa inhibitors indirectly decrease platelet aggregation by reducing thrombin formation.
  • Apixaban and rivaroxaban are predominately metabolized via the CYP450 system; however, betrixaban and edoxaban undergo only minimal metabolism via the CYP450 system.
  • Apixaban, betrixaban, edoxaban, and rivaroxaban are all substrates of the efflux transporter P-gp.[52815][60374][60375][60376][60377][60379][60380][60381][62037]

 

Vitamin K Antagonists

  • Warfarin indirectly inhibits anticoagulation by inhibiting the synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulant proteins C and S.
  • Warfarin non-competitively inhibits the C1 subunit of vitamin K epoxide reductase (VKORC1) enzyme blocking the cyclic conversion of the inactive oxidized vitamin K epoxide to active reduced vitamin K hydroquinone. A decrease in reduced vitamin K limits the activation of the vitamin K-dependent coagulant proteins (factors II, VII, IX, and X).
  • Warfarin has a delayed onset of action and complete clinical response may require 3 to 4 days of therapy.  
  • During initial therapy, warfarin may induce a hypercoagulable state due to reductions in proteins C and S activities.
  • At therapeutic warfarin doses, liver production of active vitamin K-dependent clotting factors is reduced by 30% to 50%.
  • Warfarin’s anticoagulant effects are stereoselective with the S-isomer being 3 to 5 times more potent than the R-isomer.
  • The CYP450 isoenzymes involved in the metabolism of warfarin include 2C9, 2C19, 2C8, 2C18, 1A2, and 3A4, with 2C9 being the primary enzyme that metabolizes S-warfarin.
  • Genetic polymorphisms in either the VKORC1 enzyme or CYP2C9 isoenzyme will impact the clinical effectiveness and metabolism of warfarin; thus, specific dose recommendations exist for variants.[52815][60378][60380][60382]

 

Comparative Pharmacokinetics

 

Factor Xa Inhibitors

Direct Thrombin Inhibitors

Coumarin Anticoagulants

 

Apixaban

Betrixaban

Edoxaban

Rivaroxaban

Dabigatran

Warfarin

Tmax

3 to 4 hours

3 to 4 hours

1 to 2 hours

2 to 4 hours

1 to 2 hours

72 to 96 hours

Half-life

12 hours

19 to 27 hours

10 to 14 hours

5 to 9 hours

12 to 17 hours

20 to 60 hours

Dose Frequency

Twice Daily

Once daily

Once Daily

Once Daily

Once or Twice Daily

Once Daily

Protein Binding

87%

60%

55%

92% to 95%

35%

97%

Renal Elimination

27%

11%

50%

33%

80%

0%

Food Effects

No effect

To be taken with food

No effect

Doses more than 10 mg to be taken with food

High fat meal delays absorption

Vitamin K containing foods alter clinical effect

Routine Monitoring

No

No

No

No

No

Yes

PT/INR

Reversal Agent

Factor Xa, inactivated

Not Available

Not Available

Factor Xa, inactivated

Idarucizumab

Vitamin K

Therapeutic Use

  • Drug Selection

    • Factors to assess prior to prescribing an oral anticoagulant
      • Indication
        • Atrial Fibrillation
          • Warfarin is FDA-approved for patients with atrial fibrillation and mitral stenosis or prosthetic heart valve.
        • Mechanical heart valves
          • In the RE-ALIGN trial, there was an increased incidence of both thromboembolic events (valve thrombosis, stroke, and myocardial infarction) and major bleeding with dabigatran vs. warfarin therapy among patients with bileaflet mechanical heart valves; thus, dabigatran is contraindicated for patients with mechanical prosthetic heart valves.[60397]
          • Apixaban, betrixaban, edoxaban, and rivaroxaban have not been studied in patients with prosthetic heart valves and are not FDA-approved for use in this patient population.
        • Treatment of DVT or PE
          • Dabigatran, edoxaban, and warfarin require initial 5 to 10 days therapy with a parenteral anticoagulant.
        • Cardiovascular (CV) event risk reduction
          • Apixaban in combination with aspirin is FDA-approved to reduce the risk of major CV events (i.e., CV death, myocardial infarction, and stroke) in patients with chronic coronary artery disease or peripheral artery disease. The apixaban dose is 2.5 mg twice daily with aspirin 75 mg to 100 mg once daily.
      • Compliance
        • The short half-lives of novel oral anticoagulants may be a disadvantage to patients noncompliant with medication therapy, as missed doses will increase the risk of thromboembolic complications.
        • Routine laboratory monitoring is required with warfarin therapy due to a narrow therapeutic window, interpatient dose-response variability, unpredictable pharmacokinetics, and large number of drug-drug and drug-food interactions.
      • Drug Interactions
        • All of the oral anticoagulants have the potential for significant drug-drug interactions with concomitant therapy; however, betrixaban, edoxaban, and dabigatran may have fewer interactions overall and be preferred in patients on multiple drugs or requiring frequent changes in concomitant drug therapy.
      • Patient's Bleeding Risk
        • If the patient is at higher risk for bleeding, apixaban, dabigatran, rivaroxaban, or warfarin may be preferred as they have FDA-approved reversal agents.

 

Prevention of Stroke and Systemic Embolism with Nonvalvular Atrial Fibrillation

 

Factor Xa Inhibitors

Direct Thrombin Inhibitors

Coumarin Anticoagulants

 

Apixaban

Betrixaban

Edoxaban

Rivaroxaban

Dabigatran

Warfarin

Usual Dose

5 mg twice daily

Not Indicated

60 mg once daily

20 mg once daily with the evening meal

150 mg twice daily

Initial

2 mg to 5 mg once daily j,k

 

Dose adjusted to INR = 2 to 3

(target 2.5)

 

Hepatic Impairment

Severe:

Not recommended

 

Moderate and Severe:

Not recommended

Moderate and Severe:

Avoid Use

No recommended dose adjustment

No recommended dose adjustment

Renal Impairment

  

CrCl more than 95 mL/minute

Avoid Use

 

CrCl 15 to 50 mL/minute

30 mg once daily

 

CrCl less than 15 mL/minute

Not recommended

CrCl 50 mL/minute or less

15 mg once daily with the evening meal

 

CrCl 15 to 30 mL/minute

75 mg twice daily

 

CrCl less than 15 mL/minute or dialysis

Dosing recommendations not available

 

No recommended dose adjustment

Age and Weight

Any 2 of the following: age 80 years or older, bodyweight 60 kg or less, and/or SCr 1.5 mg/dL or more

 

Reduce dose to 2.5 mg twice daily

 

Weight 60 kg or less

30 mg once daily

 

   

Dose Adjustment for Drug Interactions

P-gp and strong CYP3A4 inhibitors a, b

 

Reduce dose by 50%a,b

  

P-gp and strong CYP3A inhibitorsa, b

Avoid concomitant administration

 

P-gp and strong CYP3A inducersd

Avoid concomitant administration

 

P-gp and moderate CYP3A inhibitors and CrCl 15 to less than 80 mL/minute

Not recommended unless benefit outweighs risk

P-gp inhibitor therapy(dronedarone or ketoconazole)g

 

CrCl 30 to 50 mL/minute

75 mg twice daily

 

CrCl less than 30 mL/minute

Avoid concomitant administration

 

Dose adjustment may be required due to drug interactions or dietary vitamin K intake.

 

Treatment of Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE)

 

Factor Xa Inhibitors

Direct Thrombin Inhibitors

Coumarin Anticoagulants

 

Apixaban

Betrixaban

Edoxaban

Rivaroxaban

Dabigatran

Warfarin

Usual Dose

10 mg twice daily for 7 days, then

5 mg twice daily

Not Indicated

60 mg once daily

15 mg twice daily with food for initial 21 days, then 20 mg once daily with foode

150 mg twice daily

Initial

2 mg to 5 mg once daily j,k

 

Dose adjusted to INR = 2 to 3

(target 2.5).

 

Need for initial parenteral anticoagulant

No

 

Yes,

5 to 10 days

No

Yes,

5 to 10 days

 

Yes,

at least 5 days until the INR is 2 to 3 for 2 days or more

Hepatic Impairment

Severe: Not recommended

 

Moderate and Severe: Not recommended

Moderate and Severe: Avoid Use

No recommended dose adjustment

No recommended dose adjustment

Renal Impairment

No recommended dose adjustment

 

CrCl 15 to 50 mL/minute

30 mg once daily

 

CrCl less than 15 mL/minute

Use not recommended

CrCl less than 15 mL/minute

Avoid use

 

CrCl less than 30 mL/minute or dialysis

Dosing recommendations not availableh

No recommended dose adjustment

Age and Weight

  

Weight 60 kg or less

30 mg once daily

   

Dose Adjustment for Drug Interactions

P-gp and strong CYP3A4 inhibitors a, b

 

Reduce dose by 50%a,b

 

P-gp Inhibitors

 

30 mg once daily

P-gp and strong CYP3A inhibitorsa

Avoid concomitant administration

 

P-gp and strong CYP3A inducersd

Avoid concomitant administration

 

P-gp and moderate CYP3A inhibitors and CrCl 15 to less than 80 mL/minute

Not recommended unless benefit outweighs risk

P-gp inhibitor therapy and CrCl less than 50 mL/minute

Avoid concomitant administration

 

Dose adjustment may be required due to drug interactions or dietary vitamin K intake.

 

Prevention of Recurrent Deep Venous Thrombosis (DVT) and/or Pulmonary Embolism

 

Factor Xa Inhibitors

Direct Thrombin Inhibitors

Coumarin Anticoagulants

 

Apixaban

Betrixaban

Edoxaban

Rivaroxaban

Dabigatran

Warfarin

Usual Dose

2.5 mg twice daily after at least 6 months of DVT or PE treatment

Not Indicated

Not Indicated

20 mg once daily with foode

150 mg twice daily

Initial

2 mg to 5 mg once daily j,k

 

Dose adjusted to INR = 2 to 3 (target 2.5).

 

Hepatic Impairment

Severe: Not recommended

  

Moderate and Severe: Avoid Use

No recommended dose adjustment

No recommended dose adjustment

Renal Impairment

No recommended dose adjustment

  

CrCl less than 15 mL/minute

Avoid use

 

CrCl less than 30 mL/minute or dialysis

Dosing recommendations not availableh

No recommended dose adjustment

Dose Adjustment for Drug Interactions

P-gp and strong CYP3A4 inhibitors a, b

 

Reduce dose by 50%a,b

  

P-gp and strong CYP3A inhibitorsa, b

Avoid concomitant administration

 

P-gp and strong CYP3A inducersd

Avoid concomitant administration

 

P-gp and moderate CYP3A inhibitors and CrCl 15 to less than 80 mL/minute

Not recommended unless benefit outweighs risk

P-gp inhibitors and CrCl less than 50 mL/minute

Avoid concomitant administration

 

Dose adjustment may be required due to drug interactions or dietary vitamin K intake.

 

Prevention of Deep Venous Thrombosis (DVT) After Hip Replacement

 

Factor Xa Inhibitors

Direct Thrombin Inhibitors

Coumarin Anticoagulants

 

Apixaban

Betrixaban

Edoxaban

Rivaroxaban

Dabigatran

Warfarin

Usual Dose

2.5 mg twice dailyc

Not Indicated

Not indicated

10 mg once dailyf

110 mg on day 1, then 220 mg once dailyi

Initial

2 mg to 5 mg once daily j,k, l

 

Dose adjusted to INR = 2 to 3 (target 2.5).

 

Hepatic Impairment

Severe: Not recommended

  

Moderate and Severe: Avoid Use

No recommended dose adjustment

No recommended dose adjustment

Renal Impairment

No recommended dose adjustment

  

CrCl less than 15 mL/minute

Avoid use

 

CrCl less than 30 mL/minute or dialysis

Dosing recommendations not availableh

No recommended dose adjustment

Dose Adjustment for Drug Interactions

P-gp and strong CYP3A4 inhibitors a, b

 

Avoid concomitant administration

  

P-gp and strong CYP3A inhibitorsa

Avoid concomitant administration

 

P-gp and strong CYP3A inducersd

Avoid concomitant administration

 

P-gp and moderate CYP3A inhibitors and CrCl 15 to less than 80 mL/minute

Not recommended unless benefit outweighs risk

P-gp inhibitors and CrCl less than 50 mL/minute

Avoid concomitant administration

 

Dose adjustment may be required due to drug interactions or dietary vitamin K intake.

 

Prevention of Deep Venous Thrombosis (DVT) After Knee Replacement

 

Factor Xa Inhibitors

Direct Thrombin Inhibitors

Coumarin Anticoagulants

 

Apixaban

Betrixaban

Edoxaban

Rivaroxaban

Dabigatran

Warfarin

Usual Dose

2.5 mg twice dailyc

Not Indicated

Not Indicated

10 mg once dailyf

Not Indicated

Initial

2 mg to 5 mg once daily j,k, l

 

Dose adjusted to INR = 2 to 3 (target 2.5).

 

Hepatic Impairment

Severe

Use not recommended

  

Moderate and Severe

Avoid use

 

No recommended dose adjustment

Renal Impairment

No recommended dose adjustment

  

CrCl less than 15 mL/minute

Avoid use

 

 

No recommended dose adjustment

Dose Adjustment for Drug Interactions

P-gp and strong CYP3A4 inhibitors a, b

 

Avoid concomitant administration

  

P-gp and strong CYP3A inhibitorsa

Avoid concomitant administration

 

P-gp and strong CYP3A inducersd

Avoid concomitant administration

 

P-gp and moderate CYP3A inhibitors and CrCl 15 to less than 80 mL/minute

Not recommended unless benefit outweighs risk

 

Dose adjustment may be required due to drug interactions or dietary vitamin K intake.

 

Prevention of Venous Thromboembolism in Acutely Ill Medical Patients

 

Factor Xa Inhibitors

Direct Thrombin Inhibitors

Coumarin Anticoagulants

 

Apixaban

Betrixaban

Edoxaban

Rivaroxaban

Dabigatran

Warfarin

Usual Dose

Not Indicated

 

160 mg single dose, followed by 80 mg once daily.m Take with food.

Not Indicated

10 mg once dailyn

Not Indicated

Not Indicated

Hepatic Impairment

 

Moderate and Severe

Avoid use

 

Moderate and Severe

Avoid use

  

Renal Impairment

 

CrCl 15 to less than 30 ml/minute

80 mg single dose, followed by 40 mg once daily. Take with food.m

 

CrCl less than 15 mL/minute

Avoid use

  

Dose Adjustment for Drug Interactions

 

P-gp inhibitors

80 mg single dose, followed by 40 mg once daily. Take with food.m

 

P-gp and strong CYP3A inhibitorsa

Avoid concomitant administration

P-gp and strong CYP3A inducersd

Avoid concomitant administration

P-gp and moderate CYP3A inhibitors and CrCl 15 to less than 80 mL/minute

Not recommended unless benefit outweighs risk

  

 

aExamples of medications that are both P-gp and strong CYP3A4 inhibitors are ketoconazole, itraconazole, ritonavir, indinavir, conivaptan, and clarithromycin.

bPatients already on apixaban 2.5 mg twice daily should avoid coadministration with strong inhibitors of CYP3A4 and P-gp.

cStart apixaban 12 to 24 hours post-surgery and continue for 35 days for hip replacement and 12 days for knee replacement.

dExamples of medications that are both P-gp and strong CYP3A4 inducers are carbamazepine, phenytoin, rifampin, and St. John's wort.

eRecommended for rivaroxaban to be taken at approximately the same time each day during treatment of DVT and/or PE.

fStart rivaroxaban 6 to 10 hours post-surgery once hemostasis established and continue for 35 days after hip replacement and 12 days after knee replacement.

gDose adjustment not needed when dabigatran is coadministered with other P-gp inhibitors.

hPatients with severe renal impairment (CrCl less than 30 mL/minute) were excluded from the RE-COVER, RE-NOVATE and RE-NOVATE II trials; thus, no dosing recommendations are available for this patient population.

iStart dabigatran 1 to 4 hours post-surgery once hemostasis established and continue for 28 to 35 days. If dabigatran not started on day of surgery, then start once hemostasis achieved at a dose of 220 mg once daily.

jInitial and maintenance dose varies widely among patients. Lower initial and maintenance doses should be considered for elderly, malnourished or debilitated, and Asian patients.

kFor healthy, outpatients, guidelines recommend an initial dose of 10 mg once daily for 2 days. Lower initial dose of 5 mg once daily or less may be more appropriate for geriatric, malnourished, or debilitated patients, patients with heart failure, hepatic insufficiency, or a higher bleeding risk. [51249][51251]

lContinue therapy for a minimum of 10 to 14 days after surgery; up to 35 days is recommended.

mRecommended duration of therapy is 35 to 42 days. Give with food at the same time each day.

nBegin therapy in the hospital and continue after hospital discharge for a total recommended duration of 31 to 39 days.

Comparative Efficacy

  • Meta-analyses and indirect comparisons make up the majority of evidence available to compare the safety and efficacy of dabigatran, apixaban, edoxaban, and rivaroxaban to each another; however, various head-to-head studies comparing individual agents to warfarin or low molecular weight heparin (LMWH) have been published.
  • Overall, the NOACs have been shown to have similar and, in some cases, superior efficacy to warfarin when used for stroke and venous thromboembolism (VTE) prevention in nonvalvular atrial fibrillation.[60386][60387][60388] In acutely ill medical patients with elevated D-dimer concentrations, betrixaban had similar efficacy to enoxaparin for prevention of VTE.[63231]
  • NOACs have been found to have similar efficacy to standard therapy (LMWH plus warfarin) for the treatment of DVT and/or PE and generally had fewer adverse bleeding events.[60383][60384][60385]
  • When compared to enoxaparin for the prevention of VTE in acutely ill medical patients, there was no difference in major bleeding with betrixaban.[63231]

Summary of Selected Atrial Fibrillation Trials Comparing the NOACs to Warfarin

Study

ARISTOTLE [60389]

RE-LY

[42171]

ENGAGE AF-TIMI 48

[60390]

ROCKET-AF [46409]

Sample Size

18,201

18,113

21,105

14,264

Study Medication and Dose

Apixaban 5 mg twice daily vs. Warfarin

Dabigatran 110 mg twice daily,

Dabigatran 150 mg twice daily, vs. Warfarin

Edoxaban 30 mg once daily, Edoxaban 60 mg once daily, vs. Warfarin

Rivaroxaban 20 mg once daily vs. warfarin

Dose Adjustment

Yes, at randomization

No

Yes, at randomization and throughout study

Yes, at randomization

Design

Double-blind, double-dummy, noninferiority

PROBE (dabigatran dose blinded; warfarin unblended), noninferiority

Double-blind, double-dummy, noninferiority

Double-blind, double-dummy, event-driven, noninferiority

Mean CHADS22.12.12.83.5
CHADS2

0/1: 34%

2: 35.8%

3 or more: 30.2%

0/1: 31.9%

2: 35.6%

3 or more: 32.4%

0/1: 0%

2: 48%

3 or more: 52%

0/1: less than 1%

2: 13%

3 or more: 86.9%

Patients

  • Mean Age (years)
  • Prior Stroke or TIA
  • HTN
  • Diabetes
  • CHF or LVEF

 

  • 70
  • 19%
  • 87%
  • 25%
  • 35.5%

 

  • 72
  • 20%
  • 79%
  • 23%
  • 32%

 

  • 72
  • 28%
  • 94%
  • 36%
  • 58%

 

  • 73
  • 55%
  • 91%
  • 40%
  • 62.6%
TTR (mean)

62%

64%

68%

55%

Primary Efficacy Endpoint

Stroke or systemic embolism

Stroke or systemic embolism

Stroke or systemic embolism

Stroke or systemic embolism

Primary Safety Outcome

Major hemorrhage

Major hemorrhage

Major hemorrhage

Composite of major and CRNM bleeding

Median Follow-up Period

1.8 years

2 years

2.8 years

1.9 years

Efficacy Outcomes

Stroke or systemic embolism

HR 0.79

(CI 0.66 to 0.95)

150 mg: RR 0.66

(CI 0.53 to 0.82)

110 mg: RR 0.91 (CI 0.74 to 1.11)

60 mg: HR 0.87

(CI 0.73 to 1.04)

30 mg: HR 1.13

(CI 0.96 to 1.34)

HR 0.88

(CI 0.75 to 1.03)

Ischemic Stroke

HR 0.92

(CI 0.74 to 1.13)

150 mg: RR 0.76

(CI 0.60 to 0.98)

110 mg: RR 1.11

(CI 0.89 to 1.4)

60 mg: HR 1

(CI 0.83 to 1.19)

30 mg: HR 1.41

(CI 1.19 to 1.67)

HR 0.94

(CI 0.75 to 1.17)

Hemorrhagic Stroke

HR 0.51

(CI 0.35 to 0.75)

150 mg: RR 0.26

(CI 0.14 to 0.49)

110 mg: RR 0.31

(CI 0.17 to 0.56)

60 mg: HR 0.54

(CI 0.38 to 0.77)

30 mg: HR 0.33

(CI 0.22 to 0.5)

HR 0.59

(CI 0.37 to 0.93)

All-Cause Death

HR 0.89

(CI 0.80 to 0.99)

150 mg: RR 0.88

(CI 0.77 to 1)

110 mg: RR 0.91

(CI 0.8 to 1.03)

60 mg: HR 0.92

(CI 0.83 to 1.01)

30 mg: HR 0.87

(CI 0.79 to 0.96)

HR 0.85

(CI 0.7 to 1.02)

Safety Outcomes

Major Bleeding

HR 0.69

(CI 0.6 to 0.8)

150 mg: RR 0.93

(CI 0.81 to 1.07)

110 mg: RR 0.8

(CI 0.69 to 0.93)

60 mg: HR 0.80

(CI 0.71 to 0.91)

30 mg: HR 0.47

(CI 0.41 to 0.55)

HR 1.04

(CI 0.9 to 1.2)

Intracranial Bleeding

HR 0.42

(CI 0.3 to 0.58)

150 mg: RR 0.4

(CI 0.27 to 0.6)

110 mg: RR 0.31

(CI 0.2 to 0.47)

60 mg: HR 0.47

(CI 0.34 to 0.63)

30 mg: HR 0.3

(CI 0.21 to 0.43)

HR 0.67

(CI 0.47 to 1.93)

Gastrointestinal Bleeding

HR 0.89

(CI 0.7 to 1.15)

150 mg: RR 1.5

(CI 1.19 to 1.89)

110 mg: RR 1.1

(CI 0.86 to 1.41)

60 mg: HR 1.23

(CI 1.02 to 1.5)

30 mg: HR 0.67

(CI 0.53 to 0.83)

Rivaroxaban: 3.2%

Warfarin:

2.2%*

*Rivaroxaban versus warfarin, p less than 0.001

Oral Anticoagulants Comparative Efficacy Trials

Citation/Study

Design/Regimen

Results

Conclusion

Atrial Fibrillation
Verdecchia P, et al. Expert Opin Drug Saf 2015;14:7-20. [60386]

Bayesian meta-analysis of 4 studies (RE-LY, ROCKET AF, ARISTOTLE and ENGAGE AF-TIMI 48) to compare the safety and efficacy of the nonvitamin K antagonist oral anticoagulants [NOACs](dabigatran, apixaban, and edoxaban) and warfarin for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

 

 

Compared to Warfarin

Primary outcome (all stroke and systemic embolism [SE]) and all strokes lower with apixaban and dabigatran 150 mg.

 

Ischemic stroke lower with dabigatran 150 mg.

 

Major bleeding events lower with apixaban, dabigatran 110 mg, edoxaban 30 mg, and edoxaban 60 mg; similar with dabigatran 150 mg, rivaroxaban, and warfarin.

 

Gastrointestinal (GI) bleeds lower with edoxaban 30 mg.

 

No difference in myocardial infarction (MI) between NOACs and warfarin.

 

Probability Ranking

Major and GI Bleeds: edoxaban 30 mg first option, apixaban second and rivaroxaban last.

 

Intracranial bleeds: dabigatran 110 mg and edoxaban first options; warfarin last option.

 

Fewer MIs: rivaroxaban first option.

 

Composite Stroke/SE, all strokes and ischemic stroke: dabigatran 150 mg first option and edoxaban 30 mg last option.

 

Warfarin worst for all-cause mortality and had nil probability of ranking first for any efficacy or safety outcome.

Edoxaban 30 mg ranked best for safety but worst for all strokes and ischemic strokes.

 

Apixaban second best based on incidence of major bleeding and GI bleeding events.

 

Rivaroxaban best for MI, but worst for major and GI bleeding events.

 

Dabigatran 150 mg best and apixaban second best for composite stroke/SE, all strokes, and ischemic strokes.

 

Warfarin found to have worst efficacy and safety profile.

Venous Thromboembolism (VTE) -  DVT and/or Pulmonary Embolism
Hirschi M, et al. Vasa 2014;43:353-364. [60385]

Meta-analysis to compare the safety and efficacy of the NOACs to standard therapy and an indirect comparison of the NOACs in the treatment of acute VTE.

 

Dabigatran and Edoxaban Studies

  • 5 days or more of LMWH or UFH heparin given as initial therapy

Apixaban Study

  • Initial dose 10 mg twice daily for 7 days, then 5 mg twice daily

Rivaroxaban Study

  • Initial dose 15 mg twice daily for 3 weeks, then 20 mg once daily

NOACs vs. VKAsa

Efficacyb

D: 1.09 (CI 0.76 to 1.57)

A: 0.84 (CI 0.60 to 1.18)

E: 0.89 (CI 0.71 to 1.12)

R: 0.9 (CI 0.68 to 1.20)

 

Number of deaths:

D: 1.00 (CI 0.67 to 1.50)

A: 0.79 (CI 0.53 to 1.19)

E: 1.00 (CI 0.57 to 1.76)

R: 0.97 (CI 0.73 to 1.27)

 

Major Bleeding Events: 

D: 0.73 (CI 0.48 to 1.10)

A: 0.31(CI 0.17 to 0.55)

E: 0.85 (CI 0.60 to 1.21)

R: 0.55 (CI 0.38 to 0.81)

 

Composite Bleedingc

D: 0.63 (CI 0.51 to 0.77)

A: 0.44(CI 0.36 to 0.55)

E: 0.81 (CI 0.71 to 0.93)

R: 0.94 (CI 0.82 to 1.07)

 

ARR Major Bleedingd

D: 0.5 (CI -0.2 to 1.3)

A: 1.3 (CI 0.7 to 1.8)

E: 0.2 (CI -0.3 to 0.8)

R: 0.8 (CI 0.3 to 1.3)

 

ARR Composite Bleeding

D: 3.2 (CI 1.8 to 4.66)

A: 5.4(CI 4.1 to 6.8)

E: 1.9 (CI 0.7 to 3.2)

R: 0.6 (CI -0.7 to 1.9)

 

NOACs vs. NOACse

No significant differences in recurrent symptomatic VTE and death between NOACs.

 

Major Bleeding

Significantly lower with apixaban vs. dabigatran 0.42 (CI 0.21 to 0.86) and edoxaban 0.36 (CI 0.18 to 0.71).

 

No significant differences between apixaban and rivaroxaban.

 

Composite Bleeding

Dabigatran superior to rivaroxaban and edoxaban.

 

Apixaban superior to all NOACs.

No significant differences between NOACs and VKAs in recurrent symptomatic VTE or number of deaths.

 

Major bleeding events significantly less with apixaban and rivaroxaban compared to VKAs.

 

Combined major bleeding and clinically relevant non-major bleeding events significantly less with dabigatran, apixaban, and edoxaban compared to VKAs.

 

Only edoxaban had significantly fewer fatal bleeding and intracranial bleeding events compared to VKAs.

 

All NOACs similar efficacy in preventing recurrent VTE and death.

No difference in major bleeding with apixaban and rivaroxaban.

 

Apixaban superior to dabigatran and edoxaban in major bleeding events.

 

Apixaban superior to all other NOACs in composite bleeding events; dabigatran superior to edoxaban and rivaroxaban.

Prevention of VTE Post-Orthopedic Surgery
Gomez-Outes A, et al. BMJ 2012;344:e3675. [60391]Systematic review, meta-analysis and indirect treatment comparison of dabigatran, rivaroxaban, and apixaban versus enoxaparin for prevention of VTE following total hip or knee replacement surgery.

NOACs vs. Enoxaparinb

Symptomatic VTE

D: 0.71 (CI 0.23 to 2.12; p = 0.54)

R: 0.48 (CI 0.31 to 0.75; p = 0.001)

A: 0.82(CI 0.41 to 1.64; p = 0.57)

 

Clinically Relevant Bleeding

D: 1.12 (CI 0.94 to 1.35; p = 0.21)

R: 1.25 (CI 1.05 to 1.49; p = 0.01)

A: 0.82(CI 0.69 to 0.98; p = 0.03)

Rivaroxaban significantly reduced risk of symptomatic VTE compared to enoxaparin.

 

Risk of VTE similar with dabigatran and apixaban compared to enoxaparin.

 

Rivaroxaban significantly increased risk of clinically relevant bleeding compared to enoxaparin.

 

Compared to enoxaparin, the risk of clinically relevant bleeding was similar with dabigatran, but reduced with apixaban.

Prevention of VTE in Acutely Ill Medical Patients
Cohen AT, et al. N Engl J Med 2016; 375:534-44.[63231]APEX clinical trial for the treatment of VTE in acutely ill medical patients with betrixaban vs. enoxaparin.

Asymptomatic and symptomatic VTE:

Cohort 1
(elevated D-dimer):

Betrixaban: 0.81 (CI 0.65 to 1; p = 0.054)

Cohort 2:

Betrixaban: 0.8 (CI 0.66 to 0.98; p = 0.03)

Overall population:

Betrixaban: 0.76 (CI 0.63 to 0.92; p = 0.006)

Major bleeding

Overall population:

Betrixaban: 1.19 (CI 0.67 to 2.12; p = 0.55)

Major or clinically relevant nonmajor bleeding

Overall population:

Betrixaban: 1.97 (CI 1.44 to 2.68; p less than 0.001)

Compared to enoxaparin, betrixaban significantly reduced occurrence of asymptomatic and symptomatic VTE in the overall population; however, this was not true for the cohort population with elevated D-dimer concentrations.

Betrixaban had a significantly greater risk of major or nonmajor clinically relevant bleeding compared to enoxaparin.

No difference in occurrence of major bleeding.

 

Note: Patients with renal dysfunction received enoxaparin 20 mg which is below recommended dose of 30 mg for VTE prophylaxis in renally impaired patients.

aVKAs = vitamin K antagonists; results given as relative risk [RR] (95% confidence interval [CI]). Primary efficacy endpoint was recurrent, symptomatic VTE. D = dabigatran, A = apixaban, E = edoxaban, and R = rivaroxaban. Composite bleeding events were major bleeding events plus clinically relevant non-major bleeding events. ARR = absolute risk reduction. Indirect comparisons were performed between the NOACs to compare safety and efficacy; results given as RR (95% CI).

bD = dabigatran, R = rivaroxaban, and A = apixaban. Results for NOACs vs. enoxaparin provided as RR (95% CI)

Adverse Reactions/Toxicities

Bleeding

Bleeding events are the most common adverse reactions associated with oral anticoagulant therapy. Overall, the novel oral anticoagulants (NOACs) are associated with a lower incidence of bleeding events; however, differences may exist between the medications. In atrial fibrillation trials, the rates of life-threatening bleeding, intracranial bleeding, and non-major, clinically relevant bleeding events were lower with NOACs compared to warfarin. A meta-analysis of atrial fibrillation trials found the rate of major bleedings events was lower with apixaban, dabigatran 110 mg, and edoxaban compared to warfarin.[42171][46409][60386][60389][60390][60403][60404]

 

In treatment of VTE (DVT and/or PE) studies, dabigatran, apixaban, edoxaban, and rivaroxaban were associated with fewer bleeding events compared to warfarin. Results of meta-analyses suggest that apixaban may be associated with the lowest incidence of bleeding events; however, further investigation is needed. [60384][60388][60405][60406]

 

For the prevention of VTE following total knee or hip replacement, the incidence of major bleeding and clinically relevant bleeding events were found to be similar with enoxaparin, dabigatran, apixaban, and rivaroxaban.  However, there was a trend of more major bleeding events with rivaroxaban compared to enoxaparin and less clinically relevant bleeding events with apixaban.[60407]

 

In a study of patients with acute medical illness receiving betrixaban or enoxaparin for the prevention of VTE, betrixaban use was associated with more major or clinically relevant nonmajor bleeding events compared to enoxaparin.[63231]

 

Gastrointestinal Bleeding

The rate of gastrointestinal bleeding may be lowest with edoxaban 30 mg. In clinical trials and meta-analyses, dabigatran 150 mg twice daily, edoxaban 60 mg once daily, and rivaroxaban were associated with higher rates of gastrointestinal bleeding when compared to warfarin.[42171][46409][60386][60390][60403][60404][60408]

Cardiovascular

Data are conflicting regarding the risk of myocardial infarction (MI) with dabigatran compared to warfarin. An increased rate of MI has been reported with dabigatran compared to warfarin in some clinical trials and meta-analyses. In contrast, the FDA-conducted, observational, cohort study found the rate of MI to be similar with dabigatran and warfarin.[42171][57177][60398][60399]

Tissue Necrosis

Skin necrosis is an uncommon but serious adverse reaction to warfarin therapy that typically occurs between the third and eighth day of therapy. Skin necrosis is a result of local thrombosis. Warfarin-associated skin necrosis may be severe, requiring debridement or amputation of the affected tissue, limb, breast, or penis.[28549]

Systemic Atheroemboli and Cholesterol Microemboli

Warfarin may enhance the release of atheromatous plaque emboli leading to systemic cholesterol microembolization. Sequelae may include organ impairment/necrosis, rash, myalgia, abdominal pain, gangrene, purple-toe syndrome, cerebral ischemia, spinal cord infarction, and death. Kidney, pancreas, spleen, and liver are the most commonly involved visceral organs. Purple-toe syndrome typically occurs 3 to 10 weeks or later after the start of warfarin therapy. Discontinuation of warfarin is recommended when any of these conditions occur.[28549]

Drug Interactions

Cytochrome P-450 (CYP) and P-glycoprotein (P-gp) Substrates

Medication

CYP Substrate

P-gp Substrate

Apixaban

Major

CYP3A4

 

Minor

CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2J2

Yes

Betrixaban

No

Yes

Dabigatran

No

Yes

Edoxaban

No

Yes

Rivaroxaban

Major

CYP3A4 and CYP3A5

 

Minor

CYP2J2

Yes

Warfarin

Major for S-Warfarin

CYP2C9

 

Minor for S-Warfarin

CYP2C19, CYP2C8, CYP2C18, CYP1A2, CYP3A4

 

Major for R-Warfarin

CYP1A2 and CYP3A4

 

Minor for R-Warfarin

CYP2C19

No

Drugs that inhibit, induce, or are substrates of CYP450 isoenzymes

Warfarin is a substrate of the cytochrome P450 (CYP450) system). Most of the drug interactions involving warfarin result from inhibition or induction of the CYP450 enzymes. The major isoenzymes involved are CYP2C9, CYP1A2, CYP3A4 and minor isoenzymes are CYP2C19, CYP2C8 and CYPC18. Caution is advised if warfarin is coadministered with substrates, inhibitors, or inducers of these enzymes; dosage adjustment may be required.[28549] Apixaban and rivaroxaban are also substrates of the CYP450 system; thus, drug interactions may occur when coadministered with substrates, inducers, or inhibitors of the CYP isoenzymes.[44854][52739]

Drugs that inhibit or induce P-glycoprotein (P-gp)

Apixaban, betrixaban, dabigatran, edoxaban, and rivaroxaban are all substrates of the P-glycoprotein (P-gp) efflux system and as such may interact with drugs that inhibit or induce P-gp.[42121][44854][52739][58685][62037]

Drugs that are dual CYP3A4 and P-gp inducers

Avoid concomitant administration of apixaban or rivaroxaban and dual strong CYP3A4 and P-gp inducers due to decreased therapeutic effect of apixaban or rivaroxaban and increased risk of stroke.[44854][52739]

Drugs that are dual CYP3A4 and P-gp inhibitors

Avoid concomitant administration of rivaroxaban with strong CYP3A4 and P-gp inhibitors. Reduce the dose of apixaban to 2.5 mg twice daily when coadministered with a dual strong CYP3A4 and P-gp inhibitor. For patients already on apixaban 2.5 mg twice daily, avoid concomitant administration with dual strong CYP3A4 and P-gp inhibitors.[44854][52739]

Drugs that increase the risk of bleeding

Bleeding is the greatest risk of oral anticoagulants. The risk of bleeding is increased when used with other drugs that affect the coagulation system, although in some clinical situations, the additive effects are desirable. Additive risk of bleeding may occur when oral anticoagulants are coadministered with other oral anticoagulants, heparin, thrombolytics, platelet inhibitors, mifepristone, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and nonsteroidal anti-inflammatory drugs (NSAIDs). Occasionally short-term coadministration of edoxaban with other anticoagulants, platelet inhibitors, and thrombolytic agents may be necessary; however, long-term coadministration is not recommended.[28549][58685][63240]

Vitamin K

Vitamin K competitively antagonizes warfarin resulting in the reversal or reduction of anticoagulant activity. Exogenous administration or occult sources of vitamin K may interact with warfarin therapy. Patients should be educated on the importance of dietary balance and potential risks of dietary extremes and ingestion of nutritional supplements.[28549]

Safety Issues

Bleeding

A major risk of oral anticoagulant therapy is bleeding. All of the oral anticoagulants are contraindicated for use in patients with active pathological bleeding. Factors that may increase the risk of bleeding include concomitant therapy with other drugs that affect hemostasis, drug interactions, renal impairment, and hepatic impairment. Warfarin is also contraindicated in patients with conditions that may result in uncontrolled bleeding. Caution is advised when these agents are used in patients with any disease state associated with an increased risk of hemorrhage.[28549][42121][44854][52739][58685][62037]

Spinal Hematoma

Epidural or spinal hematoma, which may result in long-term or permanent paralysis, may occur in patients receiving oral anticoagulant therapy and neuraxial anesthesia (spinal/epidural anesthesia) or undergoing spinal puncture. If an epidural or spinal anesthesia/analgesia or lumbar puncture occurs while on oral anticoagulant therapy, monitor patients frequently for signs and symptoms of neurological impairment.[42121][44854][52739][58685][62037]

Premature Discontinuation

Avoid the abrupt discontinuation of apixaban, dabigatran, edoxaban, and rivaroxaban in the absence of adequate anticoagulation. Premature discontinuation of these oral anticoagulants may increase the risk of ischemic events, such as stroke. If therapy must be discontinued for reasons other than pathological bleeding or treatment completion, consider therapy with an alternative anticoagulant.[42121][44854][52739][58685] NOACs have short half-lives; hence, alternative anticoagulation during temporary interruption is not needed in the majority of situations. For warfarin, stop therapy approximately 5 days prior to a procedure and initiate heparin or low molecular weight heparin (LMWH) 24 hours or more after the first missed dose of warfarin. Guidelines recommend starting heparin or LMWH when INR is less than 2 in those with nonvalvular atrial fibrillation, or if INR is not measured, after omitting 2 to 3 doses of warfarin. Discontinue heparin 4 to 6 hours prior to procedure if the aPTT is within normal range. Administer the last dose of LMWH approximately 24 hours before a procedure, potentially longer in those with renal dysfunction. If necessary, residual anticoagulation can be assessed by checking aPTT (for heparin) or antifactor Xa concentrations. In most cases, warfarin can be restarted in the first 12 to 24 hours after the procedure at the patient’s usual therapeutic dose; post-procedural bridging can be considered in patients with moderate or high risk of stroke or thromboembolic events.[51785][63236]

Pregnancy

Warfarin is contraindicated in pregnancy, except for women with mechanical heart valves who are at high risk of thromboembolism. Warfarin has been shown to cause major congenital malformations (warfarin embryopathy), especially when taken during the first trimester after the sixth week of gestation. When taken during pregnancy, warfarin may cause fetal hemorrhage, spontaneous abortion, fetal mortality, and teratogenic CNS effects, such as Dandy-Walker malformation, dorsal midline dysplasia, midline cerebral atrophy, and ventral midline dysplasia. There are no adequate or well-controlled studies in pregnant women for apixaban, betrixaban, dabigatran, edoxaban, or rivaroxaban. Due to increased risk of hemorrhage, use novel oral anticoagulants during pregnancy or delivery only if potential benefit outweighs the potential risk to the mother and fetus.[28549][42121][44854][52739][58685][62037]

Genetic Polymorphisms

Patients with genetic polymorphisms of CYP2C9 and VKORC1 may require lower maintenance dosages of warfarin and more frequent INR monitoring may be necessary.[28549]

Protein C or Protein S Deficiency

Warfarin may produce a transient hypercoagulable state when administered to patients with either a protein C or protein S deficiency, which may result in skin and/or tissue necrosis. Concomitant administration of heparin for the first 5 to 7 days of warfarin therapy may reduce the risk of skin and/or tissue necrosis.[28549]

Anticoagulant Reversal

Specific agents for reversal of anticoagulation with betrixaban and edoxaban are not currently available. Vitamin K or phytonadione is FDA-approved for warfarin-induced prothrombin deficiency; intravenous vitamin K administration is recommended for warfarin reversal in major bleeding events while oral administration is recommended in nonmajor bleeding events that require hospitalization. Idarucizumab, a monoclonal antibody, is indicated for reversal of dabigatran’s anticoagulant effect for patients who require emergency surgery or urgent procedures and those with life-threatening or uncontrolled bleeding. Factor Xa, inactivated is indicated for the reversal of the anticoagulant effects of apixaban and rivaroxaban for patients experiencing life-threatening or uncontrolled bleeding. Guidelines suggest the use of 4-factor prothrombin complex concentrate (PCC) for major bleeding in patients taking a vitamin K antagonist or factor Xa inhibitor and in patients taking dabigatran, if idarucizumab is not available.[22934][51249][60212][63132][63244]

Geriatric Patients

The dose of apixaban may need to be reduced if used for nonvalvular atrial fibrillation in patients 80 years and older.[52739] According to the Beers Criteria, apixaban should be avoided in geriatric patients with a creatinine clearance less than 25 mL/minute due to an increased risk of bleeding. The dose of edoxaban and rivaroxaban should be reduced in geriatric patients with a creatinine clearance in the range of 30 to 50 mL/minute due to an increased risk of bleeding. The Beers expert panel recommends avoiding edoxaban and rivaroxaban in geriatric patients with a creatinine clearance less than 30 mL/minute. Additionally, avoid edoxaban in geriatric patients with a creatinine clearance more than 95 mL/minute. The creatinine clearance threshold for which the Beers expert panel recommends avoiding use of apixaban, edoxaban, and rivaroxaban is based on clinical trial exclusion criteria and may not be the same as that in the product labeling. Dabigatran is a potentially inappropriate medication (PIM) in patients 75 years of age and older and caution is recommended since there is a greater risk of bleeding than with warfarin and reported rates with other target-specific oral anticoagulants. In addition, there is a lack of evidence of efficacy and safety in patients with a creatinine clearance less than 30 mL/minute and the Beers expert panel recommends avoiding dabigatran in this patient population due to an increased risk of bleeding.[60515] Betrixaban use in geriatric patients was not associated with any clinically significant safety or effectiveness differences in clinical trials.[62037]

Antiphospholipid Antibody Syndrome

Apixaban, dabigatran, and rivaroxaban are not recommended in patients with antiphospholipid antibody syndrome and a history of thrombosis. Patients that are triple positive, meaning positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies, may be at an increased risk for recurrent thrombotic events with direct oral anticoagulant (DOAC) therapy compared to vitamin K antagonist therapy. The Rivaroxaban in Antiphospholipid Syndrome (RAPS) study compared continued warfarin therapy to rivaroxaban therapy in patients with antiphospholipid antibody syndrome (with or without systemic lupus erythematosus) who experienced a previous, single venous thromboembolism. Based on the surrogate endpoints, endogenous thrombin potential and thrombin generation, the authors concluded that rivaroxaban may be a potential option in this patient population.[64416] In contrast, the Trial on Rivaroxaban in AntiPhospholipid Syndrome (TRAPS), which compared the safety and efficacy of rivaroxaban and warfarin in patients with triple positive antiphospholipid antibody syndrome at high-risk for thromboembolic events, was prematurely terminated secondary to the higher rate of thromboembolic and major bleeding events with rivaroxaban compared to warfarin.[64417] Results from a meta-analysis concluded that the risk of recurrent thrombosis was greater with DOAC therapy compared to warfarin therapy in patients with antiphospholipid antibody syndrome. DOAC therapy in patients that were triple positive had an associated 4-fold increase in recurrent thrombosis. In addition, patients with a history of arterial thrombosis that received factor Xa inhibitor therapy also had an increased risk of recurrent thrombosis.[64418] Data from case reports and cohort studies have conflicting results on the safety and efficacy of DOAC therapy in patients with antiphospholipid antibody syndrome.[64419]

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