The Use of Edoxaban in Patients with Nonvalvular Atrial Fibrillation and Venous Thromboembolism: A Pharmacist's Perspective

Abstract

Until 2010, the vitamin K antagonist warfarin was the only available oral anticoagulant for the prevention of stroke or systemic embolic events (SEE) in patients with nonvalvular atrial fibrillation (NVAF) and the treatment of venous thromboembolism (VTE) in the United States. Despite its proven efficacy, the use of warfarin is limited by numerous disadvantages, including a delayed onset of action and variable efficacy resulting from interactions with genetic and environmental factors. Consequently, optimal anticoagulation with warfarin requires dose adjustments based on frequent monitoring. In contrast to warfarin, direct oral anticoagulants (DOACs) including dabigatran, rivaroxaban, apixaban, and edoxaban have predictable pharmacokinetic profiles, few drug-drug interactions, no known interactions with food, and can be administered at fixed doses without the requirement for routine monitoring. All DOACs have received US Food and Drug Administration (FDA) approval for the prevention of stroke or SEE in patients with NVAF and the treatment of VTE based on phase 3 trials demonstrating that they are at least as efficacious as warfarin. In addition, the incidence of clinically relevant bleeding associated with DOACs is comparable to or lower than with warfarin. In this article, the preclinical and clinical data that led to the FDA approval of once-daily edoxaban in January 2015 are presented. Furthermore, practical considerations for edoxaban use including dosing recommendations, transitions of care, reversal of anticoagulation, precautions, contraindications, and cost-effectiveness are discussed. Edoxaban is an important addition to oral anticoagulation options available for the therapeutic management of patients with NVAF or VTE.

Introduction

Oral anticoagulants are used to reduce the risk of stroke and systemic embolic events (SEE) in patients with nonvalvular atrial fibrillation (NVAF) and to treat venous thromboembolism (VTE).^1,2 For several decades, the vitamin K antagonist (VKA) warfarin was the only available oral anticoagulant for the management of patients with NVAF and VTE in the United States.^1-3 Although effective, warfarin therapy has several disadvantages, including a delayed onset of action, a variable drug response due to cytochrome p450 2C9 (CYP2C9) and vitamin K oxide reductase complex 1 (VKORC1) polymorphisms, and food-drug and drug-drug interactions.^3,4 The variable effects of warfarin coupled with its narrow therapeutic range necessitate dose adjustments based on frequent monitoring.^3,4 These limitations led to the development of direct oral anticoagulants (DOACs).

DOACs include the thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban.^5-8 Inhibition of factor Xa impedes thrombin generation and consequently interferes with thrombus (clot) formation. ⁹ Unlike warfarin, DOACs have a rapid onset of action, predictable pharmacokinetics (PK), and few drug interactions ( Table 1 ).^5-8 They are administered at fixed doses, without the requirement for routine monitoring. Clinical trials examining the efficacy of DOACs in preventing stroke and SEE in patients with NVAF and for the treatment of acute VTE have demonstrated that DOACs are at least as effective as warfarin.^10-19 Clinically relevant bleeding rates associated with DOAC administration were lower than or similar to those observed with warfarin use.^10-19 Furthermore, among patients with NVAF, DOACs are associated with a lower incidence of intracranial bleeding – a potentially fatal complication of anticoagulation – compared with warfarin.^12-14,17 Rivaroxaban and apixaban are approved for prophylaxis of deep vein thrombosis (DVT) following hip or knee replacement surgery,^6,7 whereas all 4 DOACs are indicated for the reduction of stroke risk in patients with NVAF and for the treatment of VTE.^5-8 In light of the recent approval of edoxaban in the United States, ⁸ Switzerland, ²⁰ the European Union, ²¹ and Japan, ²² this article summarizes key findings from preclinical and clinical studies of edoxaban and provides a practical perspective on the incorporation of edoxaban into the therapeutic management of patients with NVAF or VTE.

Table 1.

Comparison of pharmacokinetic parameters of direct oral anticoagulants.^5-8

	Dabigatran	Rivaroxaban	Apixaban	Edoxaban
Mechanism of action	Thrombin inhibitor	Factor Xa inhibitor	Factor Xa inhibitor	Factor Xa inhibitor
Absolute bioavailability, %	3-7	Variable a	50	62
Time to peak concentration, hours	1-3 b	2-4	3-4	1-2
Half-life, hours	12-17	5-9 c	~12	10-14
Renal clearance	80% of absorbed dose	66% of oral dose	27% of absorbed dose	50% of absorbed dose
Substrate of P-gp	Yes	Yes	Yes	Yes
Substrate of CYP3A4	No	Yes	Yes	Yes d

Note: CYP3A4 = cytochrome P450 3A4; P-gp = P-glycoprotein.

^aThe bioavailability of rivaroxaban is dependent on dosage and food intake; 80%-100% of a 10-mg dose is bioavailable independent of food consumption, while the bioavailability of a 20-mg dose is approximately 66% under fasting conditions, and higher with food intake. The 15-mg and 20-mg doses must be administered with food.

^bTime to peak concentration is 1 hour under fasting conditions and 3 hours after a high-fat meal.

^cThe half-life of rivaroxaban is 5-9 hours for healthy subjects aged 20-45 years old and 11-13 hours for the elderly.

^dEdoxaban undergoes minimal metabolism by CYP3A4.

Pharmacokinetics

Edoxaban, a direct and selective inhibitor of free factor Xa as well as Xa incorporated into the prothrombin complex, ²³ exhibits approximately dose-proportional PK in healthy subjects administered single (10 mg to 150 mg) or multiple (60 mg to 120 mg) doses. ²⁴ Upon oral administration of edoxaban, 61.8% of a 60-mg dose is absorbed, and peak edoxaban plasma concentrations are attained approximately 1 to 2 hours postdose.^8,25 Edoxaban undergoes minimal metabolism as nearly 72.9% of a 60-mg oral dose is eliminated unchanged. ²⁶ The terminal half-life of oral edoxaban is 10 to 14 hours, and approximately 50% of the absorbed dose is renally cleared.^8,25 Since edoxaban is a substrate of the transporter P-glycoprotein (P-gp), concomitant administration of P-gp inhibitors such as verapamil, erythromycin, and ketoconazole increases edoxaban exposure, while the P-gp inducer rifampin reduces exposure.^8,27-32

Nonvalvular Atrial Fibrillation

Dose-finding Study

A preliminary 12-week, phase 2, dose-finding study evaluated the safety of edoxaban 30 mg once-daily, 60 mg once-daily, 30 mg twice-daily, and 60 mg twice-daily doses in comparison with dose-adjusted warfarin (international normalized ratio [INR], 2.0-3.0) among NVAF patients. ³³ The incidence of major or clinically relevant nonmajor (CRNM) bleeding observed with the 30-mg once-daily (3.0%) or 60-mg once-daily (3.8%) dose was comparable with warfarin (3.2%), while edoxaban 30 mg twice-daily (7.8%) and 60 mg twice-daily (10.6%) doses were associated with higher rates of major or CRNM bleeding than warfarin. ³³ Bleeding correlated more closely with trough edoxaban concentrations than peak plasma concentrations; for a total daily dose of 60 mg, the major and CRNM bleeding rate observed in the 60 mg once-daily dosing group was less than half that observed in the 30 mg twice-daily group, indicating that once-daily dosing, which is associated with lower trough concentrations relative to twice-daily dosing, was a safer dosing regimen. ³³ Similarly, population PK modeling and exposure-response analysis performed using data from a total of 15 phase 1 and phase 2 studies identified trough edoxaban concentrations as a predictor of bleeding incidence and demonstrated that edoxaban 30 mg once-daily and 60 mg once-daily doses were associated with a lower incidence of bleeding relative to other doses of edoxaban among patients with NVAF. ³¹ In addition, this analysis identified moderate renal impairment (creatinine clearance [CrCL] 30-50 mL/min) and concomitant P-gp inhibitor use as factors associated with increased exposure and elevated bleeding risk. ³¹ In a phase 2 study involving Japanese patients with NVAF, low body weight (≤60 kg) correlated with increased bleeding upon treatment with edoxaban. ³⁴ Based on these findings, edoxaban 30 mg once-daily and 60 mg once-daily dosing regimens, including a 50% dose reduction for patients with any of the risk factors mentioned above, were selected for further evaluation in the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48) trial. ¹³

Clinical Outcomes

The ENGAGE AF-TIMI 48 study – a randomized, phase 3 trial – examined the efficacy and safety of edoxaban treatment compared with dose-adjusted warfarin in patients with NVAF and a moderate-tohigh stroke risk. ¹³ Patients with a CHADS₂ (congestive heart failure, hypertension, age ≥75 years, diabetes, prior stroke or transient ischemia) score of 2 or greater were randomized to receive edoxaban 30 mg once daily (lower-dose regimen), 60 mg once daily (higher-dose regimen), or dose-adjusted warfarin (INR, 2.0-3.0). ¹³ Those with moderate renal impairment (CrCL 30-50 mL/min), with a body weight of 60 kg or less, or receiving concomitant P-gp inhibitors were administered a dose 50% lower than the assigned edoxaban dose. The median durations of treatment and follow-up were 2.5 and 2.8 years, respectively. When compared with warfarin, both the lower-dose and the higher-dose edoxaban groups were noninferior at preventing stroke or SEE, the primary efficacy endpoint ( Table 2A ). ¹³ The incidence of major bleeding, the primary safety endpoint, was lower for both the lower-dose and the higher-dose edoxaban groups compared with the warfarin group ( Table 2A ). ¹³ Fewer episodes of intracranial bleeding and lifethreatening bleeding were observed with both edoxaban regimens relative to warfarin treatment, although there was a greater incidence of gastrointestinal bleeding for the higher-dose group ( Table 2A ). ¹³

Table 2.

Efficacy and safety endpoints in the (A) ENGAGE AF-TIMI 48^8,13 and (B) Hokusai-VTE trial ¹⁵

(A) ENGAGE AF-TIMI 48
	Lower-dose edoxaban vs warfarin HR (95% CI)	Higher-dose edoxaban vs warfarin HR (95% CI)
Primary efficacy endpoint a
Stroke or SEE during treatment period
Full cohort	1.07 (0.87-1.31) b	0.79 (0.63-0.99) c
Patients with CrCL ≤95 mL/min	—	0.68 (0.55-0.84)
Primary safety endpoint
Major bleeding	0.47 (0.41-0.55) d	0.80 (0.71-0.91) d
Intracranial	0.30 (0.21-0.43) d	0.47 (0.34-0.63) d
Gastrointestinal	0.67 (0.53-0.83) d	1.23 (1.02-1.50) e

Note: Lower-dose edoxaban = 30 mg daily and higher-dose edoxaban = 60 mg daily. For both regimens, edoxaban dose was reduced by 50% in patients with low body weight (≤60 kg), with renal impairment (CrCL 30-50 mL/min), or receiving strong P-glycoprotein inhibitors. CI = confidence interval; CrCL = creatinine clearance; ENGAGE AF-TIMI 48 = Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48; HR = hazard ratio; SEE = systemic embolic event.

^aA 97.5% confidence interval was used for the primary efficacy endpoint.

^bNoninferiority analysis (P = .005).

^cNoninferiority analysis (P < .001).

^dStatistically significant difference between edoxaban and warfarin groups (P < .001).

^eStatistically significant difference between edoxaban and warfarin groups (P = .03).

Note: Edoxaban dose = 60 mg daily; patients with low body weight (≤60 kg), creatinine clearance of 30-50 mL/min, or receiving strong P-glycoprotein inhibitors were administered a 30-mg daily dose. CI = confidence interval; CRNM = clinically relevant nonmajor; HR = hazard ratio; VTE = venous thromboembolism.

^aNoninferiority analysis (P < .001).

^bSuperiority analysis (P = .004).

A subgroup analysis of patients by renal function indicated that the higher-dose regimen was comparable with warfarin at preventing strokes or SEE among patients with CrCL of 30 to 50 mL/min. ³⁵ In patients with CrCL greater than 50 to less than 80 mL/min, the higher-dose group was associated with fewer strokes or SEE than warfarin, while there was a trend toward fewer strokes or SEE with warfarin treatment compared with the higher-dose group among patients with CrCL greater than or equal to 80 mL/min. Further analysis indicated that among patients with normal renal function (CrCL ≥80 mL/min), higher-dose edoxaban was at least as effective as warfarin up to CrCL of 95 mL/min ( Table 2A ); at CrCL rates exceeding 95 mL/min, higher-dose edoxaban was associated with a worse outcome with regard to the prevention of stroke or SEE among patients when compared with well-managed warfarin. Warfarin achieved greater stroke or SEE prevention than the lower-dose group among patients with CrCL greater than or equal to 80 mL/min, and a similar trend was observed among patients with CrCL equal to 30 to less than 50 mL/min. The incidence of ischemic stroke was higher with the lower-dose edoxaban group than warfarin among patients with CrCL greater than or equal to 80 mL/min. In patients with CrCL greater than 50 to less than 80 mL/min, the lower-dose regimen was comparable to warfarin at stroke or SEE prevention, whereas ischemic stroke incidence was numerically higher with the lower-dose edoxaban group than warfarin. ³⁵ Based on these findings, oncedaily edoxaban 60 mg was approved for the reduction of stroke and SEE risk in NVAF patients with CrCL greater than 50 to less than or equal to 95 mL/min. ⁸ A 30-mg dose is recommended for patients with CrCL 15 to 50 mL/min. ⁸

Venous Thromboembolism

Dose Selection

Earlier studies examined the efficacy of edoxaban for VTE prevention across a range of doses.^36,37 A phase 2 study evaluated the efficacy of once-daily edoxaban 15 mg, 30 mg, 60 mg, and 90 mg at preventing VTE in patients undergoing total hip replacement in comparison with the low-molecular-weight heparin (LMWH) dalteparin once daily (5,000 international units [IU] following an initial dose of 2,500 IU). ³⁶ All doses of edoxaban tested were more effective than dalteparin at VTE prevention. The rate of VTE incidence was 28.2%, 21.2%, 15.2%, and 10.6% for edoxaban 15 mg, 30 mg, 60 mg, and 90 mg, respectively, while VTE occurred in 43.8% of patients treated with dalteparin. Bleeding rates were low and similar regardless of treatment regimen. Another phase 2 study involving Japanese patients undergoing total knee arthroplasty demonstrated that the incidence of VTE was 29.5%, 26.1%, 12.5%, and 9.1% among patients receiving edoxaban 5 mg, 15 mg, 30 mg, and 60 mg, respectively, compared with 48.3% among placebo-treated patients. ³⁷ Consistent with these studies, a pharmacometric analysis of multiple studies revealed that the reduction in VTE incidence upon edoxaban treatment was dose dependent in patients undergoing total hip replacement. ³⁸ These observations, together with findings from the NVAF phase 2 trials, led to the selection of the 60-mg once-daily dose for further evaluation in the Hokusai-VTE trial. ³⁹

Clinical Outcomes

The phase 3 Hokusai-VTE study investigated the efficacy and safety of edoxaban in comparison with warfarin in VTE-diagnosed patients. ¹⁵ Patients with confirmed DVT or pulmonary embolism (PE) were randomized and received either edoxaban 60 mg once daily or dose-adjusted warfarin, following initial treatment with enoxaparin or unfractionated heparin for 5 days or longer in accordance with guidelines. ¹ Similar to the ENGAGE AF-TIMI 48 trial, patients with a body weight less than or equal to 60 kg, CrCL 30 to 50 mL/min, or receiving concomitant P-gp inhibitors were administered a 50% reduced dose of 30 mg edoxaban. All patients were followed for 12 months, irrespective of treatment duration, which ranged from 3 to 12 months depending upon the physician's judgment. For the primary efficacy endpoint of recurrent VTE or VTE-related death, edoxaban was noninferior to warfarin ( Table 2B ). ¹⁵ Edoxaban was superior to warfarin with regard to major or CRNM bleeding, the primary safety endpoint ( Table 2B ). ¹⁵

As a result of findings from this study, edoxaban 60 mg was approved for the treatment of DVT and PE. ⁸ In patients with a body weight less than or equal to 60 kg, CrCL 15 to 50 mL/min, or taking concomitant P-gp inhibitors, a 30-mg dose is recommended.

Special Clinical Considerations

Liver Impairment

Administration of a single, 15-mg dose of edoxaban did not increase exposure to the drug in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. ⁴⁰ The use of edoxaban is contraindicated in patients with moderate or severe liver impairment (Child-Pugh B or C classification), although edoxaban may be administered to patients with mild hepatic impairment (Child-Pugh A). ⁸

Hemodialysis

Hemodialysis in patients with end-stage renal disease did not significantly alter exposure to edoxaban, indicating that an additional dose of the drug may not be necessary for patients following hemodialysis. ^8,41 Furthermore, hemodialysis does not effectively decrease plasma edoxaban concentrations, ⁴¹ which may be required in patients in need of immediate, invasive interventions.

Drug Interactions

In anticipation of elevated plasma edoxaban exposure upon concomitant administration of P-gp inhibitors such as quinidine, verapamil, and dronedarone, ²⁹ patients in the ENGAGE AF-TIMI 48 trial were administered a 50% reduced dose in the presence of P-gp inhibitors. ¹³ However, results from this trial indicated that plasma edoxaban trough concentrations were lower among patients receiving the lower dose in comparison with patients administered the full dose.^35,42 As a consequence of this finding and because prevention of debilitating cardioembolic stroke is of greater concern than the risk of bleeding, ⁴³ a dose reduction is not recommended among patients with NVAF who are receiving concomitant P-gp inhibitors. ⁸ However, a reduced dose of 30 mg is recommended for the treatment of patients with VTE taking concomitant strong P-gp inhibitors such as verapamil, quinidine, azithromycin, clarithromycin, erythromycin, oral itraconazole, and oral ketoconazole. ⁸

Edoxaban is contraindicated for NVAF and VTE patients receiving the P-gp inducer rifampin, which decreases plasma edoxaban exposure.^8,32 Concomitant administration of aspirin or nonsteroidal antiinflammatory drugs (NSAIDs) with edoxaban is associated with an increase in bleeding times when compared with the administration of a single agent.^8,44 Therefore, patients taking aspirin or NSAIDs need to be carefully monitored.

Monitoring

Although dosing of edoxaban based on the clinical features of the patient has been demonstrated to obviate the need for monitoring, ⁴² measurement of anticoagulant activity may be necessary in some circumstances, including severe bleeding and perioperative management. The measurement of anti-FXa activity is a reliable method to monitor the anticoagulant activity of edoxaban, but is limited by variability at plasma concentrations greater than 200 to 300 ng/mL. ⁴⁵ Thrombin generation assay is sensitive to plasma edoxaban concentrations, while prothrombin time and activated partial thromboplastin time are less sensitive, despite correlating with edoxaban levels.^45,46

Reversal

Rapid reversal of anticoagulation may be required in the event of bleeding, which is a risk associated with anticoagulation. Although as a class, DOACs are associated with fewer bleeding events when compared with warfarin, specific reversal agents have only recently become available^5,47 or are in late-stage development. ⁴⁸ In the case of minor bleeding, withdrawing DOAC treatment or delaying it may suffice. ⁴⁹ Moderate bleeding may be managed with supportive measures including mechanical compression, blood transfusion, and fluid resuscitation. ⁴⁹ Administration of prothrombin complex concentrates (PCC) or recombinant factor VIIa to reverse oral factor Xa inhibitors may be considered in the event of life-threatening bleeding based on preliminary data demonstrating the effectiveness of these antidotes on rivaroxaban and edoxaban.^50-53 The effect of PCC on dabigatran reversal remains unclear, with an ex vivo study suggesting an increase in thrombin time upon the addition of PCC to blood samples collected from dabigatran-treated subjects ⁵¹ and an in vivo human study reporting the lack of an effect of PCC on coagulation parameters including activated partial thromboplastin time, endogenous thrombin potential lag time, thrombin clotting time, and ecarin clotting time among subjects receiving dabigatran. ⁵⁰ Idarucizumab, a monoclonal antibody fragment, is effective for rapid dabigatran reversal ⁵⁴ and recently received US Food and Drug Administration approval for reversing the anticoagulant effects of dabigatran for emergency surgery or urgent procedures, or in life-threatening situations or cases of uncontrolled bleeding. ⁴⁷ Neutralizing agents in development include the small molecule PER977 (ciraparantag) and the catalytically inactive FXa decoy PRT064445 (andexanet alfa).^55-57 Two recent trials demonstrated that andexanet alfa was effective at reversing the anticoagulant effects of rivaroxaban and apixaban in healthy older adults. ⁴⁸

Transitions of Care

Drug-to-Drug Transition

Patients transitioning to edoxaban from warfarin may commence edoxaban treatment upon discontinuation of warfarin when INR is less than or equal to 2.5. Those receiving other DOACs or LMWH can start edoxaban treatment during the next scheduled dose or administration following discontinuation of current anticoagulant. Patients receiving unfractionated heparin may start treatment with edoxaban 4 hours after the discontinuation of infusion. ⁸

The ENGAGE AF-TIMI 48 trial was unique among studies evaluating the efficacy of DOACs at preventing stroke or SEE in NVAF patients because it incorporated a transition plan from study drug to VKA or other DOACs at the end of the study. ⁵⁸ As a result, stroke or SEE rates during the transition period were comparable among the higher- and lower-dose edoxaban- and warfarin-treated groups.^13,58 Based on this trial experience, recommendations for transitioning from edoxaban to other anticoagulants have been developed. For patients switching from edoxaban to warfarin, a lower dose of 30 mg or 15 mg is recommended for patients receiving edoxaban 60 mg or dose-reduced 30 mg, respectively, upon the start of concurrent warfarin administration. ⁸ Edoxaban use should be discontinued upon stabilization of INR greater than or equal to 2, which should be measured at least weekly just prior to the administration of edoxaban. Alternatively, the transition to warfarin may progress by discontinuing edoxaban and administering parenteral anticoagulants with warfarin at the next scheduled edoxaban dose. When a stable INR greater than or equal to 2 is achieved, parenteral anticoagulation should be discontinued and oral anticoagulation with warfarin alone should commence. Patients transitioning from edoxaban to other DOACs or parenteral anticoagulation must discontinue edoxaban and begin anticoagulation with these agents at the next scheduled edoxaban dose. ⁸

Surgery and other Interventions

Edoxaban should be withheld for at least 24 hours prior to invasive or surgical procedures. ⁸ This is in contrast to warfarin, for which current guidelines recommend withdrawal of the drug for at least 5 days prior to planned surgery. ⁵⁹ In addition, for patients receiving warfarin, bridging anticoagulation is recommended among those with an elevated risk of thromboembolism, while it is deemed unnecessary for those with a low risk of developing thromboemboli.^59,60 Anticoagulation with edoxaban may be resumed as soon as hemostasis is achieved after surgery, ⁸ whereas warfarin can be restarted 12 to 24 hours after the procedure and under hemostatic conditions. ⁵⁹

Contraindications and Warnings/Precautions

Active pathological bleeding is an absolute contraindication for edoxaban. ⁸ Discontinuation of edoxaban in the absence of alternative anticoagulation must be avoided as it increases the risk of stroke or SEE. As with other DOACs, edoxaban treatment may increase the risk of spinal or epidural hematoma in patients undergoing spinal or epidural puncture or administered neuraxial anesthesia. Consequently, the risk–benefit analysis of spinal procedures must be carefully considered in patients receiving edoxaban. Indwelling epidural or intrathecal catheters should not be removed for at least 12 hours after the last administered edoxaban dose. Administration of edoxaban should not commence for 2 hours after catheter removal. Edoxaban is not recommended for patients with mechanical heart valves or mitral stenosis, as it has not been evaluated in these populations. Edoxaban should not be used in NVAF patients with CrCL greater than 95 mL/min. ⁸

Cost

A recent analysis indicated that edoxaban use in NVAF patients is estimated to reduce medical costs by $340 per patient compared with warfarin therapy. ⁶¹ Among NVAF and acute VTE patients combined, edoxaban treatment was estimated to result in a $6.6 million cost reduction for a hypothetical population of 1 million insured lives compared with treatment with warfarin or placebo. ⁶¹ Similarly, modeling based on ENGAGE AF-TIMI 48 data revealed that higher-dose edoxaban (60 mg) treatment resulted in greater lifetime cost savings compared with warfarin ($42,846 vs $27,094). ⁶² In patients with VTE, edoxaban treatment lowered costs by $344 compared with standard therapy. ⁶³

Conclusions

Oral anticoagulation with warfarin mitigates the risk of stroke or SEE in patients with NVAF and effectively treats VTE. However, therapeutic management with warfarin is challenging due to its narrow therapeutic range and unpredictable drug response, resulting from numerous interactions with genetic and environmental factors. Unlike warfarin, DOACs, which are as effective as warfarin for the treatment of VTE and prevention of stroke or SEE in patients with NVAF, exhibit a stable pharmacokinetic profile and do not require routine monitoring. Additionally, rates of clinically relevant bleeding associated with DOAC use are similar to or lower than those associated with warfarin use. Edoxaban – the most recently approved DOAC – provides a more convenient, safer, and more cost-effective alternative to warfarin and may improve therapeutic outcomes for patients with NVAF or VTE.