DrugClassOverview

Oral Anticoagulants

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Aug.28.2023

Oral Anticoagulants

Summary

Direct-acting oral anticoagulants (DOACs) include direct thrombin inhibitors (e.g., dabigatran) and factor Xa inhibitors (e.g., apixaban, edoxaban, and rivaroxaban).
Warfarin has a slower onset of action and longer half-life compared to the DOACs.
Routine laboratory monitoring is required with warfarin therapy, but not generally needed with DOACs.
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 DOACs as compared to warfarin.
Anticoagulation reversal agents are available for apixaban, dabigatran, rivaroxaban, and warfarin, but not for 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, 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, edoxaban undergo only minimal metabolism via the CYP450 system.
Apixaban, edoxaban, and rivaroxaban are all substrates of the efflux transporter P-gp.[52815][60374][60375][60376][60377][60379][60380][60381]

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	Edoxaban	Rivaroxaban	Dabigatran	Warfarin
Tmax	3 to 4 hours	1 to 2 hours	2 to 4 hours	1 to 2 hours	72 to 96 hours
Half-life	12 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 or Twice Daily	Once Daily
Protein Binding	87%	55%	92% to 95%	35%	97%
Renal Elimination	27%	50%	33%	80%	0%
Food Effects	No effect	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	Yes PT/INR
Reversal Agent	Factor Xa, inactivated	Not Available	Factor Xa, inactivated	Idarucizumab	Vitamin K

Therapeutic Use

Drug Selection
- Factors to assess prior to prescribing an oral anticoagulant
  - Indication
    - Atrial Fibrillation
      - Oral anticoagulant therapy is recommended for men with a CHA₂DS₂-VASc score of 2 or greater or women with a score of 3 or greater. Anticoagulation therapy may be considered in men with a CHA₂DS₂-VASc score of 1 or women with a score of 2.[65848][66740]
      - Apixaban, dabigatran, edoxaban, and rivaroxaban are FDA-approved for stroke and systemic embolism prophylaxis in patients with nonvalvular atrial fibrillation.
      - Warfarin is FDA-approved for the treatment and prevention of thromboembolic complications associated with atrial fibrillation and mitral stenosis or prosthetic heart valve.
      - For eligible atrial fibrillation patients, DOACs (i.e., apixaban, dabigatran, edoxaban, rivaroxaban) are preferred over warfarin therapy.[65847][65848][66740]
      - For patients with end-stage renal disease, apixaban, rivaroxaban, or warfarin may be potential options.[65847][65848][66796][66797][66798]
      - The HAS-BLED score may be used to determine if a patient is at high risk of adverse bleeding events. For patients with a HAS-BLED score of 3 or greater, consider therapy with an oral anticoagulant with a low bleeding risk, such as apixaban, dabigatran 110 mg, or edoxaban.[65847]
      - The SAMe-TT₂R₂ score aids is assessing if a patient will do well on warfarin therapy. A score of 0 to 2 indicates that a patient will do well on either warfarin or a DOAC; however, a score greater than 2 indicates that an DOAC is preferred over warfarin.[65847][66740]
    - 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, edoxaban, and rivaroxaban have not been studied in patients with prosthetic heart valves, are not FDA-approved or recommended for use in this patient population.[65847][65848][66740]
    - 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
  - 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 the oral anticoagulants have the potential for significant drug-drug interactions with concomitant therapy; however, 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	Edoxaban	Rivaroxaban	Dabigatran	Warfarin
Usual Dose	5 mg twice daily	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	At least 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	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^o	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	At least 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 inhibitors^{a, b} Avoid concomitant administration P-gp and strong CYP3A inducers^d 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	Edoxaban	Rivaroxaban	Dabigatran	Warfarin
Usual Dose	10 mg twice daily for 7 days, then 5 mg twice daily	60 mg once daily	15 mg twice daily with food for initial 21 days, then 20 mg once daily with food^e	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 available^h	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 inhibitors^a Avoid concomitant administration P-gp and strong CYP3A inducers^d 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	Edoxaban	Rivaroxaban	Dabigatran	Warfarin
Usual Dose	2.5 mg twice daily after at least 6 months of DVT or PE treatment	Not Indicated	20 mg once daily with food^e	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 available^h	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 inhibitors^{a, b} Avoid concomitant administration P-gp and strong CYP3A inducers^d 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	Edoxaban	Rivaroxaban	Dabigatran	Warfarin
Usual Dose	2.5 mg twice daily^c	Not indicated	10 mg once daily^f	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 available^h	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 inhibitors^a Avoid concomitant administration P-gp and strong CYP3A inducers^d 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	Edoxaban	Rivaroxaban	Dabigatran	Warfarin
Usual Dose	2.5 mg twice daily^c	Not Indicated	10 mg once daily^f	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 inhibitors^a Avoid concomitant administration P-gp and strong CYP3A inducers^d 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	Edoxaban	Rivaroxaban	Dabigatran	Warfarin
Usual Dose	Not Indicated	Not Indicated	10 mg once daily^m	Not Indicated	Not Indicated
Hepatic Impairment			Moderate and Severe Avoid use
Renal Impairment			CrCl less than 15 mL/minute Avoid use
Dose Adjustment for Drug Interactions			P-gp and strong CYP3A inhibitors^a Avoid concomitant administration P-gp and strong CYP3A inducers^d 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.

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

^oPatients with a CrCl less than 30 mL/minute were not included in atrial fibrillation clinical trials; however, rivaroxaban serum concentrations with a 15 mg once daily dose are expected to be similar to patients with moderate renal impairment. The American Heart Association/American College of Cardiology/Heart Rhythm Society atrial fibrillation guidelines recommend avoiding rivaroxaban in patients with a CrCl less than 15 mL/minute due to lack of data on benefits outweighing the risks of therapy.[44854][65848]

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 DOACs 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]
DOACs 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]

Summary of Selected Atrial Fibrillation Trials Comparing the DOACs 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 CHADS₂	2.1	2.1	2.8	3.5
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 DOACs to standard therapy and an indirect comparison of the DOACs 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	*DOACs vs. VKAs^a* *Efficacy^b* 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 Bleeding^c:* 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 Bleeding^d 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) *DOACs vs. DOACs^e* No significant differences in recurrent symptomatic VTE and death between DOACs. 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 DOACs.	No significant differences between DOACs 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 DOACs 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 DOACs 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.	DOACs vs. Enoxaparin^b *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.

^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 DOACs to compare safety and efficacy; results given as RR (95% CI).

^bD = dabigatran, R = rivaroxaban, and A = apixaban. Results for DOACs 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 DOACs 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 DOACs 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]

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
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, 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]

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]

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]

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] DOACs 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 when INR is no longer therapeutic. 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 intravenous heparin 2 to 6 hours and subcutaneous heparin 12 to 24 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 (for heparin or LMWH). 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][66343]

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, dabigatran, edoxaban, or rivaroxaban. Due to increased risk of hemorrhage, use DOACs during pregnancy or delivery only if potential benefit outweighs the potential risk to the mother and fetus.[28549][42121][44854][52739][58685]

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 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

For individuals 80 years and older, the dose of apixaban should be reduced if they also have a serum creatinine of 1.5 mg/dL or more and/or weigh 60 kg or less.[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]

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 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]

[22934]AquaMephyton (phytonadione, vitamin K1) package insert. Buena, NJ: Teligent Pharma, Inc. 2018 Mar.

[28549]Coumadin (warfarin tablets) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2017 Aug.

[42121]Pradaxa (dabigatran) oral capsules package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2023 Nov.

[42171]Connolly SJ, Ezekowitz MB, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.

[44854]Xarelto (rivaroxaban) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2023 Feb.

[46409]Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91.

[51249]Holbrook A, Schulman S, Witt DM, et al. Evidence-Based Management of Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e152S-e184S.

[51251]Ageno W, Gallus AS, Wittkowsky A, et al. Oral Anticoagulant Therapy Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST 2012;141:44S-88S.

[51785]Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: American College of Physicians evidence-based clinical practice guidelines (9th Edition). CHEST 2012;141:e326S-350S.

[52739]Eliquis (apixaban) package insert. Bristol-Myers Squibb Company; Princeton, NJ. 2021 Apr.

[52815]Scaglione F. New Oral Anticoagulants: Comparative Pharmacology with Vitamin K Antagonists. Clin Pharmacokinet 2013. Epub ahead of print, doi: 10.1007//s40262-012-0030-9.

[57177]Food and Drug Administration Drug Information Update. Pradaxa (dabigatran etexilate mesylate): FDA study of Medicare patients finds risks lower for stroke and death but higher for gastrointestinal bleeding with Pradaxa (dabigatran) compared to warfarin. Retrieved May 13, 2014. Available on the World Wide Web http://www.fda.gov/Drugs/DrugSafety/ucm396470.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery

[58685]Savaysa (edoxaban) package insert. Basking Ridge, NJ: Daiichi Sankyo, Inc.; 2023 Oct.

[60212]Praxbind (idarucizumab) injection. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2021 Oct.

[60374]Gonzalez-Quesada CJ, Giugliano RP. Comparison of the phase III clinical trial designs of novel oral anticoagulants versus warfarin for the treatment of nonvalvular atrial fibrillation: implications for clinical practice. Am J Cardiovasc Drugs 2014;14:111-127.

[60375]Aikens GB, Osmundson JR, Rivey MP. New oral pharmacotherapeutic agents for venous thromboprophylaxis after total hip arthroplasty. World J Orthop 2014;5:188-203.

[60376]Fontana P, Goldhaber SZ, Bounameaux H. Direct oral anticoagulants in the treatment and long-term prevention of venous thrombo-embolism. Eur Heart J 2014;35:1836-1843.

[60377]Skeik N, Murphy CJ, Porten BR. The role of novel anticoagulants in the management of venous thromboembolism. Vasc Med 2014;19:205-214.

[60378]Hull RD, Gersh M. The current landscape of treatment options for venous thromboembolism: a focus on novel oral anticoagulants. Curr Med Res Opin 2015;31:197-210.

[60379]Tun NM, Oo TH. Prevention and treatment of venous thromboembolism with new oral anticoagulants: a practical update for clinicians. Thrombosis 2013;2013:183616.

[60380]Madan S, Shah S, Partovi S, et al. Use of novel oral anticoagulant agents in atrial fibrillation: current evidence and future perspective. Cardiovasc Diagn Ther 2014;4:314-323.

[60381]Stambler BS. A new era of stroke prevention in atrial fibrillation: comparing a new generation of oral anticoagulants with warfarin. Int Arch Med 2013;6:46.

[60382]Shameem R, Ansell J. Disadvantages of VKA and requirements for novel anticoagulants. Best Pract Res Clin Haematol 2013;26:103-114.

[60383]Gomez-Outes A, Suarez-Gea ML, Lecumberri R, et al. Direct oral anticoagulants in the treatment if venous thromboembolism, with a focus on patients with pulmonary embolism: an evidence-based review. Vasc Health Risk Manag 2014;10:627-639.

[60384]Kakkos SK, Kirkilesis GI, Tsolakis IA. Editor's choice - efficacy and safety of the new oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban in the treatment and secondary prevention of venous thromboembolism: a systematic review and meta-analysis of phase III trials. Eur J Vasc Endovasc Surg 2014;48:565-575.

[60385]Hirschi M, Kundi M. New oral anticoagulants in the treatment of acute venous thromboembolism – a systematic review with indirect comparisons. Vasa 2014;43:353-364.

[60386]Verdecchia P, Angeli F, Bartolini C, et al. Safety and efficacy of nonvitamin K oral anticoagulants in nonvalvular atrial fibrillation: a Bayesian meta-analysis approach. Expert Opin Drug Saf 2015;14:7-20.

[60387]Assiri A, Al-Majzoub O, Kanaan AO, et al. Mixed treatment comparison meta-analysis of aspirin, warfarin, and new anticoagulants for stroke prevention in patients with nonvalvular atrial fibrillation. Clin Ther 2013;35:967-984.

[60388]Renda G, di Nicola M, De Caterina R. Net clinical benefit of non-vitamin K antagonist oral anticoagulants versus warfarin in phase III atrial fibrillation trials. Am J Med 2015;128:1007-1014.

[60389]Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-992.

[60390]Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-2104.

[60391]Gomez-Outes A, Terleira-Fernandez AI, Suarez-Gea L, et al. Dabigatran, rivaroxaban, or apixaban versus enoxaparin for thromboprophylaxis after total hip or knee replacement: systematic review, meta-analysis, and indirect treatment comparisons. BMJ 2012;344:e3675.

[60397]Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013;369:1206-1214.

[60398]Douxfils J, Buckinx F, Mullier F, et al. Dabigatran etexilate and risk of myocardial infarction, other cardiovascular events, major bleeding, and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc 2014;3:e000515.

[60399]Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014;129:764-772.

[60403]Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomized trials. Lancet 2014:383:955-962.

[60404]Senoo K, Lip GYH. Comparative efficacy and safety of non-vitamin K antagonist oral anticoagulants for patients with nonvalvular atrial fibrillation. Semin Thromb Hemost 2015:41:146-153.

[60405]Kang N, Sobieraj DM. Indirect treatment comparison of new oral anticoagulants for the treatment of acute venous thromboembolism. Thromb Res 2014;133:1145-1151.

[60406]Castellucci LA, Cameron C, Le Gail G, et al. Clinical and safety outcomes associated with treatment of acute venous thromboembolism: a systematic review and meta-analysis. JAMA 2014;312:1122-1135.

[60407]Nieto JA, Espada NG, Merino RG, et al. Dabigatran, rivaroxaban and apixaban versus enoxaparin for thromboprophylaxis after total knee or hip arthroplasty: pool-analysis of phase III randomized clinical trials. Thromb Res 2012;130:183-191.

[60408]Loffredo L, Perri L, Violi F. Impact of new oral anticoagulants on gastrointestinal bleeding in atrial fibrillation: a meta-analysis of interventional trials. Dig Liver Dis 2015;47:429-431.

[60515]The American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 2015;63:2227-46.

[63132]Andexxa (coagulation factor Xa [recombinant], inactivated-zhzo) injection package insert. Wilmington, DE: AstraZeneca Pharmaceuticals, LP.; 2024 Mar.

[63236]Doherty JU, Gluckman TH, Hucker WJ, et al. 2017 ACC expert consensus decision pathway for periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation: a report of the American College of Cardiology Clinical Expert Consensus Document Task Force. J Am Coll Cardiol 2017;871-898.

[63240]Habert JS. Minimizing bleeding risk in patients receiving direct oral anticoagulants for stroke prevention. Int J Gen Med. 2016; 9:337-47.

[63244]Tomaselli GF, Mahaffey KW et al. 2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology task force on expert consensus decision pathways. J Am Coll Cardiol. 2017; 70(24):3042-67.

[64416]Cohen H, Hunt BJ, Efthymiou M, et al. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol 2016;3:e426-e436.

[64417]Pengo V, Denas G, Zoppellaro G, et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood 2018;132:1365-1371.

[64418]Dufrost V, Risse J, Reshetnyak T, et al. Increased risk of thrombosis in antiphospholipid syndrome in patients treated with direct oral anticoagulants. Results from an international patient-level data meta-analysis. Autoimmun Rev 2018;17:1011-1021.

[64419]Cohen H, Efthymiou M, Isenberg DA. Use of direct oral anticoagulants in antiphospholipid syndrome. J Thromb Haemost 2018;16:1028-1039.

[65847]Lip GY, Banerjee A, Boriani G, et al. Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel report. CHEST 2018;154:1121-1201.

[65848]January CT, Wann SL, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. Circulation 2019;140:e125-e151.

[66343]Horner MA, Duane TM, Ehlers EH, et al. American College of Surgeons' guideline for the perioperative management of antithrombotic medication. J Am Coll Surg 2018;227:521-536.

[66740]Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed collaboration with the European association of cardio-thoracic surgery (EACTS). Eur Heart J 2021;42(5):373-498.

[66796]Coleman CI, Kreutz R, Sood NA, et al. Rivaroxaban versus warfarin in patients with nonvalvular atrial fibrillation and severe kidney disease or undergoing hemodialysis. Am J Med 2019;132:1078-1083.

[66797]Weir MR, Ashton V, Moore KT, et al. Rivaroxaban versus warfarin in patients with nonvalvular atrial fibrillation and stage IV-V chronic kidney disease. Am Heart J 2020;223:3-11.

[66798]Chen C, Cao Y, Zheng Y, et al. Effect of rivaroxaban or apixaban in atrial fibrillation patients with stage 4-5 chronic kidney disease or on dialysis. Cardiovasc Drugs Ther 2021;35:273-281.