Review of the Target-Specific Oral Anticoagulants in Development for the Treatment and Prevention of Venous Thromboembolism

Abstract

Anticoagulation therapy is often indicated for the treatment and prevention of venous thromboembolism (VTE). Despite advances in anticoagulant management with parenteral anticoagulants and vitamin K antagonists, limitations to their use still exists, leading to investigation of alternative anticoagulants such as factor Xa inhibitors and direct thrombin inhibitors. To date, 3 target-specific oral anticoagulants (TSOACs) are Food and Drug Administration approved; several other agents are currently in development to optimize VTE management and minimize bleeding risks. The objective of this systematic review article is to provide clinicians an overview of the clinical evidence on the investigational TSOACs for the treatment and prevention of VTE. Of the agents in development, edoxaban holds the most promise due to robust data supporting its clinical benefit with a similar bleeding risk to currently approved agents. Clinicians should understand the TSOACs under investigation, since differences in pharmacokinetics and pharmacodynamics may influence clinical decision making and agent selection for management of VTE. Currently, no direct comparisons between TSOACs have been conducted. Agents under investigation have yet to overcome the major limitations of the currently existing TSOACs. Further studies are necessary to clarify which TSOAC agent is best for management of VTE in clinical practice.

Keywords

target-specific oral anticoagulants venous thromboembolism factor Xa antagonists/inhibitors direct thrombin inhibitors factor IXa inhibitors

Introduction

Venous thromboembolism (VTE) is a common condition associated with significant morbidity and mortality.¹ Advances in anticoagulation management with the use of parenteral anticoagulants and oral vitamin K antagonists (VKAs) have proven to be highly effective in prevention of VTE recurrence. Oral VKAs are associated with a consistent and strong reduction in the risk of recurrent VTE with a relative risk (RR) reduction of ∼80% when compared to placebo (RR 0.20, 95% confidence interval [CI] 0.11-0.38), resulting in a recurrence risk of 3% while patients are on therapy.² However, they are associated with a high risk of bleeding and require frequent laboratory monitoring.³ Additional limitations of VKAs include potential for multiple clinically important drug–drug and drug–food interactions due to their narrow therapeutic index.

To overcome these limitations, 2 classes of target-specific oral anticoagulants (TSOACs) have been developed, namely, direct thrombin inhibitors (DTIs) and factor Xa (FXa) inhibitors. Clinical pharmacokinetics and pharmacodynamics for VKAs and TSOACs are summarized in Table 1.^{4

–18} DTIs prevent thrombin from cleaving fibrinogen, and FXa inhibitors prevent cleavage of prothrombin to thrombin. These agents have been studied for the treatment and prevention of VTE, prevention of stroke in patients with nonvalvular atrial fibrillation, and acute coronary syndromes.¹⁹ Currently, 3 TSOACs have been approved by the Federal Drug Administration (FDA), namely, dabigatran, rivaroxaban, and apixaban. Several randomized controlled trials have demonstrated the noninferiority of these agents when compared to warfarin for the management of VTE with comparable or lower bleeding rates.^{20

–32} Although these agents may eliminate routine outpatient laboratory monitoring, limitations of these agents exist, including lack of monitoring for anticoagulation effect at initiation, clear guidance on timing of therapy interruption for surgical procedures, complete dosing recommendations for renal and hepatic impairment, reversal agents in the setting of bleeding, and long-term efficacy and safety data.

Table 1.

Clinical Pharmacokinetics and Pharmacodynamics of Selected Novel Anticoagulants^{4

–18}.

Medication	Warfarin	Dabigatran	Rivaroxaban	Apixaban	Edoxaban
MOA	Vitamin K antagonist inhibits coagulation factors II, VII, IX, and X and proteins C and S	Selective and reversible direct thrombin inhibitor	Selective and reversible FXa inhibitor with selectivity for prothrombinase complex and clot-associated FXa	Selective, direct acting and reversible FXa inhibitor	Selective, direct, reversible FXa inhibitor
Time to peak plasma concentration	4 h	0.5-2 h	2-4 h	3-4 h	1-2 h
Onset of action	36-72 h	2-3 h	2 h	3 h	1-3 h
Half-life	20-60 h	11-14 h	9-13 h	8-15 h	8-10 h
Bioavailability	Almost 100%	6.5%	80%-100%	50%	62%
Dosing recommendations for VTE prevention^a	NA	Following orthopedic surgery: not approved	Following TKR or THR: 10 mg once daily	Following TKR or THR: 2.5 mg twice daily	Following orthopedic surgery: 30 mg once daily
Dosing recommendations for treatment and secondary prophylaxis following VTE^a	Variable, titration to goal INR 2-3	150 mg twice daily after 5-10 days of parenteral anticoagulation	15 mg twice daily for 21 days, then 20 mg once daily; prevention: 20 mg once daily	Acute VTE: 10mg twice daily for 7 days, then 5mg twice daily; Prevention: 2.5 mg twice daily	60 mg once daily
Dose adjustment considerations for treatment and secondary prophylaxis following VTE	None	CrCl <50 mL/min with concomitant p-gp inhibitor: avoid use CrCl <30 mL/min or dialysis: no recommendations available	CrCl <30 mL/min: avoid use CrCl 15-80mL/min and concomitant use of p-gp inhibitors and moderate CYP3A4 inhibitors: avoid use Moderate or severe hepatic impairment (Child-Pugh B or C): avoid use	Renal dysfunction: none Severe hepatic impairment: not recommended	CrCl 30-50 mL/min, body weight <60 kg, or concomitant potent p-gp inhibitors: 30 mg once daily
Contraindications	None	CrCl <30 mL/min	CrCl <30 mL/min; Concomitant use of P-gp and strong CYP3A4 inhibitors or inducers: avoid use	VTE treatment & secondary prevention: CrCl <25 mL/min or SCr >2.5 mg/dL: not studied TKR/THR prophylaxis: CrCL <30 mL/min: not studied	CrCl <30 mL/min excluded from studies
Metabolism	Mainly via CYP2C9 but also CYP2C19, CYP2C8, CYP2C18, CYP1A2, and CYP3A4	Not metabolized by CYP450 enzymes; bioconversion completed in liver with 20% conjugation by glucuronic acid	Enzymes CYP3A4 and CYP2J2	Catalyzed mainly by CYP3A4/5	Multiple pathways; hepatic metabolism is minor pathway
Elimination	92% renal	Up to 80% renal	66% renal, 28% fecal	Over 50% fecal, about 25% renal	50% renal
Drug interactions	CYP2C9, CYP3A4, and CYP1A2 inhibitors Dietary vitamin K	p-gp inhibitors (caution with amiodarone, verapamil, and quinidine)	CYP inhibitors p-gp inhibitors CI: HIV protease drugs, antimycotics Cautions: Rifampin, St John’s Wort Strong CYP3A4 inducers reduce plasma concentrations (rifampin, phenytoin, carbamazepine, and phenobarbital)	Strong CYP and P-gp inhibitors HIV proteases Antimycotics Cautions: Cimetidine SSRI Diltiazem	Strong P-gp inhibitors
Coagulation monitoring	INR	Not required	Not required	Not required	Not required
Adverse effects	Tissue necrosis, ICH	Dyspepsia, GI bleeding	Minor	Minor	Not sufficiently studied

Abbreviations: MOA, mechanism of action; FXa, factor Xa; TKR, total knee replacement; THR, total hip replacement; INR, international normalized ratio; VTE, venous thromboembolism; CrCl, creatinine clearance; SCr, serum creatinine; NA, not applicable; p-gp, p-glycoprotein; CYP, cytochrome P450; CI, contraindications; HIV, human immunodeficiency virus; SSRI, selective serotonin receptor inhibitor; ICH, intracranial hemorrhage; GI, gastrointestinal.

^aFor edoxaban, dosage for prevention or treatment of VTE not yet approved by Food and Drug Administration, and dosing information provided are based on phase 3 studies.

Development of novel TSOACs continues in an effort to improve efficacy and minimize bleeding risk in patients with VTE prevention and treatment. In addition to direct thrombin and FXa inhibition, different steps in the coagulation cascade are being targeted including inhibition of factor IXa, the factor-VIIa–tissue factor complex, and the factor-Va–factor VIIIa complex.³³ Additional TSOACs with similar and different mechanisms of action to those currently approved by the FDA are in development. These emerging anticoagulant agents have the potential to simplify the long-term treatment of patients. The objective of this systematic review is to provide clinicians an overview of the clinical evidence on the TSOACs currently under investigation for the treatment and prevention of VTE.

Literature Selection and Evaluation

Three independent reviewers searched the PubMed, OVID Medline, and EMBASE databases independently using the following key words: thromboembolism and one of the new agents under clinical investigation (edoxaban, betrixaban, darexaban, eribaxaban, letaxaban, TAK-442, LY517717, and TTP889). The literature search was limited to phase 2 or 3 clinical trials in human subjects ≥18 years. Only trials published in English analyzing one of the new agents under clinical investigation for the management of VTE were included for review. Trials involving agents no longer under investigation by the manufacturer were excluded.

Oral Direct FXa Inhibitors Currently Under Investigation

Edoxaban (DU-176b)

Edoxaban, the free base of DU-176b, is a direct, selective, reversible inhibitor of both free FXa and FXa bound to prothrombinase complex.^11,12,34 Edoxaban exerts its anticoagulant effect by blocking the formation of thrombin from prothrombin catalyzed by the prothrombinase complex.^13,14 Edoxaban inhibits thrombin generation and thrombus formation in a dose-dependent fashion.^12,14 Pharmacokinetic properties of edoxaban are summarized in Table 1.^{11

–18} Of note, statistically significant covariants incorporated into the pharmacokinetic modeling for edoxaban include renal function, gender, body weight, administration with food, formulation, and timing of dose postoperatively.¹⁴ Patients given edoxaban within 6 to 24 hours of major surgery have a slower absorption rate, likely related to decreased gastric motility. Administration with food slows absorption rate as well, although this is not considered to be clinically significant, thus it can be administered without regard to food.^12,14 The study design and outcome data for studies examining edoxaban for prevention and treatment of VTE have been summarized in Table 2.^11,15,17,34

Table 2.

Overview of Clinical Trials.

Trial	Study design	Inclusion criteria	Exclusion criteria	Primary end point	Efficacy outcomes	Safety outcomes
Fuji et al³⁴	Phase 2b, multicenter, randomized, placebo-controlled study	20-85 years of age Primary unilateral TKR	Risk of bleeding (history of intracranial or intraocular bleeding, gastrointestinal bleeding, or peptic ulcer) Prolonged PT or aPTT Hgb <9 g/dL Platelet count <100 ×10⁴/µL Poorly controlled blood pressure (SBP >160 mmHg or DBP >100 mm Hg) Risk of VTE (history of DVT or PE, coagulation disease, MI, CVA, or TIA) Body weight <40 kg Use of antithrombotic therapy Difficulty performing venography (SCr >1.5 mg/dL, iodine or radiocontrast dye allergy, hepatic dysfunction) Pregnancy or potential pregnancy Participation in another clinical study	Efficacy: VTE by surveillance venography or objectively confirmed symptomatic VTE post-TKR occurring up to 25-35 days after end of study treatment Safety: Composite major (life-threatening bleeding, bleeding into critical organs, decrease of Hgb >2 g/dL or transfusion >4 units of blood and/or require repeat surgery) and CRNM bleeding (hematoma ≥5 cm, epistaxis or gingival bleeding ≥5 min, GIB, gross hematuria ≥24 h, or other bleeding assessed to be clinically significant)	Edoxaban 5 mg (n = 88): 29.5% Edoxaban 15 mg (n = 92): 26.1% Edoxaban 30 mg (n = 88): 12.5% Edoxaban 60 mg (n = 88): 9.1% Placebo (n = 89): 48.3% All doses administered once daily P = .005 for each group compared to placebo; P < .001 by Cochran-Armitage test for dose–response	Primary Outcome: Edoxaban 5 mg (n = 103): 1.9% (P = .445) Edoxaban 15 mg (n = 106): 3.8% (P = 1.000) Edoxaban 30 mg (n = 103): 3.9% (P = 1.000) Edoxaban 60 mg (n = 106): 4.7% (P = 1.000) Placebo (n = 102): 3.9% (P = .270) by Cochran-Armitage test for dose–response Major bleeding: Edoxaban 5 mg (n = 103): 0% Edoxaban 15 mg (n = 106): 0% Edoxaban 30 mg (n = 103): 0% Edoxaban 60 mg (n = 106): 0.9% Placebo (n = 102): 0% CRNM bleeding: Edoxaban 5 mg (n = 103): 1.9% Edoxaban 15 mg (n = 106): 3.8% Edoxaban 30 mg (n = 103): 3.9% Edoxaban 60 mg (n = 106): 3.8% Placebo (n = 102): 3.9% Minor bleeding: Edoxaban 5 mg (n = 103): 3.9% Edoxaban 15 mg (n = 106): 6.6% Edoxaban 30 mg (n = 103): 6.8% Edoxaban 60 mg (n = 106): 12.3% Placebo (n = 102): 2.9%
Raskob et al¹⁵	Phase 2, multicenter, randomized, double-blind, and dose–response study	≥18 years of age Elective primary unilateral THR Screened within 30 days prior to surgery	Bleeding or coagulation disorder Hemorrhagic stroke or predisposing conditions (history of intraocular hemorrhage, nonhemorrhagic stroke within prior 3 months, intracranial malignancy) Gastrointestinal bleed or documented peptic ulcer within prior 3 months Abnormal baseline PT or aPTT Uncontrolled hypertension (SBP >180 mm Hg or DBP >110 mm Hg) Hgb <9 g/dL Platelet count <100 ×10⁹/L Use of anticoagulants or fibrinolytic agents within 10 days prior to study Continued use of aspirin >100 mg/d, clopidogrel, ticlopidine, dipyridamole, or NSAIDs Hypersensitivity to dalteparin, heparin, or pork products Contraindication to venography (SCr >132 μmol/L, iodine or radiocontrast dye allergy, inadequate venous access for the procedure ALT/AST ≥1.5 × ULN Elevated bilirubin Positive hepatitis A, B, or C serology GGT ≥2 × ULN Known alcohol or drug dependence within past 12 months Estimated survival <12 months Previously enrolled in study of edoxaban Pregnant or lactating Spinal or epidural analgesia and Traumatic or bloody spinal tap Indwelling epidural catheter	Efficacy: VTE by venography or objectively confirmed symptomatic VTE post-THR during treatment period Safety: composite major (fatal, decrease in Hgb >2 g/dL, transfusion ≥2 units blood, critical site, required reoperation, or cessation of study medication) or CRNM (non-major GIB, macroscopic hematuria ≥24 h, rectal bleeding, skin hematoma >25 cm², wound hematoma >150 cm², epistaxis or gingival bleeding >5 min, prolonged bleeding after venipuncture) during 10 days after first dose of study drug	Edoxaban 15 mg (n = 170): 28.2% (P = .005) Edoxaban 30 mg (n = 151): 21.2% (P < .001) Edoxaban 60 mg (n = 158): 15.2% (P < .001) Edoxaban 90 mg (n = 151): 10.6% (P < .001) Dalteparin 2500 IU LD, then 5000 IU daily (n = 144):43.8% All doses administered once daily P < .001 by Cochran-Armitage test for dose–response	Primary outcome: Edoxaban 15 mg (n = 192): 1.6% (95% CI 0.3-4.5) Edoxaban 30 mg (n = 170): 1.8% (95% CI 0.4-5.1) Edoxaban 6 mg (n = 185): 2.2% (95% CI 0.6-5.4) Edoxaban 90 mg (n = 177): 2.3% (95% CI 0.6-5.7) Dalteparin (n = 172): 0% (95% CI 0.0-2.1) P = .583 by Cochran-Armitage test for dose–response Major bleeding: Edoxaban 15 mg: 0.5% (95% CI 0.0-2.9) Edoxaban 30 mg: 0.6% (95% CI 0.0-3.2) Edoxaban 60 mg: 0.5% (95% CI 0.0-3.0) Edoxaban 90 mg: 1.1% (95% CI 0.1-4.0) Dalteparin: 0% (95% CI 0.0-2.1) CRNM bleeding: Edoxaban 15 mg: 1% (95% CI 0.1-3.7) Edoxaban 30 mg: 1.2% (95% CI 0.1-4.2) Edoxaban 60 mg: 1.6% (95% CI 0.3-4.7) Edoxaban 90 mg: 1.7% (95% CI 0.4-4.9) Dalteparin: 0% (95% CI 0.0-2.1) Minor bleeding: Edoxaban 15 mg: 0.5% Edoxaban 30 mg: 0% Edoxaban 60 mg: 2.7% Edoxaban 90 mg: 1.6% Dalteparin: 0.6%
Fuji et al¹⁷	Phase 3, multicenter, randomized, open-label, active-comparator study	≥20 years of age HFS (inner or outer femoral neck)	Increased bleeding risk (history of intracranial bleeding or recent gastrointestinal bleed) Increased risk of VTE (history of VTE, fracture or prosthetic replacement of lower limbs in prior 6 months, recent MI, CVA, or TIA) Body weight <40 kg Current use of antithrombotic therapy CrCl <30 mL/min Hepatic impairment Conditions preventing bilateral venography Pregnancy or lactation Contraindication to enoxaparin Abnormal bleeding at site of spinal anesthesia administration Abnormal or excessive bleeding during or immediately after surgery Unable to take oral medications Required additional surgery after the initial HFS until the start of study drug administration	Efficacy: VTE by surveillance venography or visually confirmed with diagnostic imagining within 24-96 h of treatment completion Safety: major (fatal, decrease in Hgb >2 g/dL, transfusion >4 units blood, critical site, requiring repeat surgery) or CRNM bleeding (hematoma ≥5 cm, epistaxis or gingival bleeding ≥5 min, GIB, hematuria >24 h, or other bleeding assessed to be clinically relevant)	Edoxaban 30 mg (n = 46) daily: 6.5% (absolute difference 2.8, 95% CI −12.4-14.2) Enoxaparin 2000 IU (20 mg) twice daily (n = 27): 3.7%	Primary outcome: Edoxaban (n = 59): 3.4% (absolute difference −3.5, 95% CI −18.8-6.0) Enoxaparin (n = 29): 6.9% Major bleeding: Edoxaban: 1.7% (absolute difference −1.8, 95% CI −15.6-6.1) Enoxaparin: 3.4% CRNM bleeding: Edoxaban:1.7% (absolute difference −1.8, 95% CI −15.6-6.1) Enoxaparin: 3.4% Minor bleeding: Edoxaban: 22% (absolute difference 11.7, 95% CI −6.5-25.5) Enoxaparin: 10.3%
Büller et al¹¹	Phase 3, multicenter, randomized, double-blind, noninferiority trial	≥18 years of age Acute, symptomatic DVT (popliteal, femoral, or iliac vein) or PE	Contraindication to heparin or warfarin Had received >48 hours of therapeutic doses of heparin Had received >1 dose of vitamin K antagonist Malignancy Another indication for warfarin Continued use of aspirin >100 mg or dual antiplatelet therapy CrCl <30 mL/min	Efficacy: adjudicated recurrent symptomatic VTE Safety: composite major (decrease in Hgb ≥2 g/dL, transfusion ≥2 units blood, critical site, fatal) and CRNM bleeding (need for medical intervention, contact with a physician, interruption of the study drug or with discomfort or impairment of activities of daily life)	Edoxaban 60 mg daily (n = 4118): 3.2% (P < .001 for noninferiority) Warfarin to goal INR 2-3 (n = 4122): 3.5% Subjects requiring edoxaban dose adjustment: Edoxaban: 3.0% Warfarin: 4.2% (HR 0.73, 95% CI 0.42-1.26) Subjects with right ventricular dysfunction: Edoxaban: 3.3% Warfarin: 6.2% (HR 0.52, 95% CI 0.28-0.98)	Primary outcome: Edoxaban (n = 4118): 8.5% (P = .004 for superiority) Warfarin (n = 4122):10.3% Subjects requiring edoxaban dose adjustment: Edoxaban: 7.9% Warfarin: 12.8% HR 0.62, 95% CI 0.44-0.86 Major bleeding: Edoxaban: 1.4% (P = .35 for superiority) Warfarin: 1.6% CRNM Bleeding: Edoxaban: 7.2% (P = .004 for superiority) Warfarin: 8.9% Minor bleeding: Edoxaban: 13.3% Warfarin: 15.4%
Turpie et al³⁶	Phase 2, multicenter, randomized study	18-75 years of age 50-120 kg Primary unilateral TKR	Women of childbearing potential Bleeding disorders Recent episode of internal bleeding High risk of bleeding Platelet count <100 ×10⁹/L Hgb <10 g/dL Hct <30% Use of antithrombotics or anticoagulants within 7 days prior to surgery and during treatment period Aspirin >325 mg/d and NSAID use strongly discouraged	Efficacy: VTE (DVT in operated leg determined by venogram or symptomatic DVT or PE confirmed by objective test) post-TKR occurring at up to days 10-14 of treatment period Safety: composite of major bleeding (fatal bleeds; bleeds involving vital organs; bleeds requiring surgical intervention or bleeding index ≥2.0)^aand CRNM bleeding	Betrixaban 15 mg (n = 70): 20% Betrixaban 40 mg (n = 65): 15.4% Enoxaparin 30 mg (n = 40): 10% All doses administered twice daily Statistical analysis not conducted	Primary outcome: Betrixaban 15 mg (n = 70): 0% Betrixaban 40 mg (n = 65): 2.4% Enoxaparin 30 mg (n = 40): 7% Major bleeds: Betrixaban 15 mg: 0% Betrixaban 40 mg: 0% Enoxaparin: 2.3% CRNM bleeding: Betrixaban 15 mg: 0% Betrixaban 40 mg: 2.4% Enoxaparin: 4.6%
Weitz et al³⁷	Phase 2, multicenter, randomized, dose-ranging study	≥18 years of age Elective primary TKR	Inherited thrombophilia disorder Bleeding diathesis Concurrent anticoagulation or antiplatelet therapy (clopidogrel, ticlopidine, dipyridamole, or aspirin >162 mg/d) Concurrent fibrinolytic therapy Use of NSAIDs with t_½ >17 hours History of intracerebral, intraocular, or gastrointestinal bleeding Active gastric or duodenal ulcer within 6 months History of VTE, MI, stroke, or TIA within 6 months Major surgery within 3 months Hypersensitivity to factor Xa inhibitors, enoxaparin or contrast dye >3 traumatic epidural or spinal punctures immediately prior to randomization Need for indwelling epidural catheter postoperatively BP >180/110 mm Hg CrCl <45 mL/min ALT >2 ×ULN Active liver disease or jaundice Hgb <10 g/dL Platelet count <100 ×10⁹/L Cancer Pregnant or lactating women Women of child bearing potential without adequate contraceptive use	Efficacy: composite of VTE (detected by venography or symptomatic DVT or nonfatal PE determined by objective testing) or all-cause mortality post-TKR, occurring during treatment period and up to 2 days after last dose of study medication Safety: major bleeding (fatal bleeding; intraocular, intracranial, intraspinal or retroperitoneal bleed; clinically overt bleeding with a decrease in Hgb ≥2 g/dL or transfusion ≥2 units of bleed or requiring surgical intervention	TAK-442 groups: 10 mg twice daily (n = 77): 39% (P = .013) 20 mg twice daily (n = 86): 38.4% (P = .014) 40 mg twice daily (n = 112): 21.4% (P < .001) 80 mg twice daily (n = 119): 14.3% (P < .001) 40 mg daily (n = 115): 23.5% (P = NS) 80 mg daily (n = 112): 26.8% (P = NS) Enoxaparin 30 mg twice daily (n = 109): 22.0%	Primary outcome: 10 mg twice daily (n = 104): 0% 20 mg twice daily (n = 128): 0.8% 40 mg twice daily (n = 162): 1.2% 80 mg twice daily (n = 161): 0% 40 mg daily (n = 162): 0% 80 mg daily (n = 160): 0.6% Enoxaparin (n = 161): 1.9% CRNM bleeding: 10 mg twice daily: 3.8% 20 mg twice daily: 1.6% 40 mg twice daily: 1.9% 80 mg twice daily: 3.7% 40 mg daily: 2.5% 80 mg daily: 1.9% Enoxaparin: 1.2% Minor bleeding: 10 mg twice daily: 6.7% 20 mg twice daily: 5.5% 40 mg twice daily: 4.9% 80 mg twice daily: 5.0% 40 mg daily: 1.9% 80 mg daily: 6.9% Enoxaparin: 5.6%
Agnelli et al³⁸	Phase 2, multicenter, randomized, double-blind, double-dummy, dose-escalation trial	18-75 years of age 50-120 kg in weight Primary unilateral TKR or THR	Clinically significant bleeding disorder Baseline INR >1.5 Platelet count <100 ×10⁹/L Recent stroke Uncontrolled hypertension Intracranial tumor Brain or spinal cord surgery Use of antithrombotic agents within 7 days Use of aspirin or NSAIDs (COX-2 inhibitor use permitted) ≤48 hours of surgery Active peptic ulcer disease SCr ≥2.0 mg/dL Baseline AST or ALT ≥2 ×ULN Total bilirubin outside of normal limits Hgb <10 g/dL Women of childbearing potential	Efficacy: VTE (DVT at end of treatment period detected by venography and objectively confirmed symptomatic DVT or PE during treatment period) post-TKR or THR at the end of the treatment period Safety: composite of major and minor bleeding. Major bleeding similar to study by Turpie et al³⁶	LY 25 mg (n = 26): 42.3% LY 50 mg (n = 20): 40% LY 75 mg (n = 22): 54.6% LY 100 mg (n = 69): 18.8% LY 125 mg (n = 80): 19.9% LY 150 mg (n = 77) 15.6% (P = .0001 for all groups compared to enoxaparin) Enoxaparin 40 mg (n = 66): 21.2% All doses administered once daily	Primary outcome: LY 25 mg (n = 32): 0% LY 50 mg (n = 34): 0% LY 75 mg (n = 32): 0% LY 100 mg (n = 106): 0.9% LY 125 mg (n = 110): 0% LY 150 mg (n = 103): 1.0% Enoxaparin (n = 90): 2.2% Major bleeding: LY 25 mg: 0% LY 50 mg: 0% LY 75 mg: 0% LY 100 mg: 0.9% LY 125 mg: 0% LY 150 mg: 0% Enoxaparin: 0%
Eriksson et al⁵²	Phase 2, multicenter, randomized, double-blind, placebo-controlled, proof-of-concept study	≥18 years Surgical repair within 72 h of unilateral hip fracture Completed 5-9 days of LMWH or UFH prior to enrollment	Any bleeding disorder Clinical signs of VTE Requirement for continued anticoagulation History of intracranial or gastrointestinal bleeding within past 3 months Active malignant disease Associated multiple trauma Body weight <45 kg Hgb <8 g/dL Hct <26% Platelet <100 000/mL AST/ALT >3 × ULN Bilirubin >1.5 × ULN SCr >180 µmol/L Use of NSAIDs discouraged Maximum aspirin dose of 325 mg/d	Efficacy: total VTE events (venographic or symptomatic DVT or PE) Safety: occurrence of bleeding events Major bleeding defined as clinically overt bleeding: associated with Hgb ≥2 g/dL or transfusion of ≥2 units of blood; fatal bleeding; retroperitoneal, intracranial, intraspinal or intraocular bleeding; and bleeding leading to reoperation CRNM bleeding: skin hematoma > 25 cm²; excessive wound hematoma; multiple source bleeding; epistaxis or gingival bleeding >5 min; macroscopic hematuria; rectal bleeding; hematemesis; and hemoptysis All other events considered minor bleeding	TTP889 300 mg once daily (n = 109): 32.1% Placebo (n = 103): 28.2% (P = .58)	No major bleeding events reported CRNM events: TTP889 300 mg (n = 129): 1.6% Placebo (n = 131): 0.8% Minor bleeding events: TTP889: 0% Placebo: 2.3%

Abbreviations: TKR; total knee replacement; PT, prothrombin time; aPTT, activated partial thromboplastin time; Hgb, hemoglobin; SBP, systolic blood pressure; DBP, diastolic blood pressure; VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolism; MI, myocardial infarction; CVA, cerebrovascular accident; TIA, transient ischemic attack; SCr, serum creatinine; TKR, total knee replacement; CRNM, clinically relevant nonmajor; GIB, gastrointestinal bleed; THR, total hip replacement; NSAIDs, nonsteroidal anti-inflammatory drugs; AST, aspartate aminotransferase; ALT; alanine aminotransferase; ULN, upper limit of normal; GGT, gamma-glutamyl transferase; LD, loading dose; HFS, hip fracture surgery; CrCl, creatinine clearance; Hct, hematocrit; t_½, half-life; BP, blood pressure; NS, not significant; INR, international normalized ratio; COX-2, cyclooxygenase-2; LMWH, low-molecular-weight heparin; UFH, unfractionated heparin; CI, confidence interval.

^aBleeding index = [units packed red cells or whole blood transfused] + [hemoglobin prebleed] − [hemoglobin postbleed].

Phase 2 dose finding studies have been conducted for the prevention of VTE after major orthopedic surgery including total knee arthoplasty (TKA) and total hip replacement (THR). A study conducted in 523 Japanese subjects undergoing TKA found that the incidence of VTE decreased with increasing edoxaban daily dosing (5 mg 29.5%, 15 mg 26.1%, 30 mg 12.5%, 60 mg 9.1% vs placebo 48.3%; P < .001) when started in the morning following the surgery and continued for 11 to 14 days.³⁴ Bilateral surveillance venography was conducted within 24 hours of study drug discontinuation, and all but 1 VTE identified were asymptomatic. One symptomatic deep vein thrombosis (DVT) was identified in a patient taking edoxaban 5 mg. The incidence of VTE was significantly lower than placebo for every dose of edoxaban studied. Rates of the primary safety outcome were low in all treatment groups with no significant difference between edoxaban doses and placebo (edoxaban 1.9%-4.7% vs placebo 4.7%; P = .270), and no dose-related effect was identified. Only 1 major bleeding event was identified in a subject from the edoxaban 60 mg treatment group. Minor bleeding was found to be dose related. Timing of dose after surgery (range 6-24 hours) did not affect rates of either bleeding or VTE.

Similarly, a study comparing the use of edoxaban (15, 30, 60, and 80 mg daily) or dalteparin (2500 IU loading dose, followed by 5000 IU subcutaneously once daily) in 903 subjects undergoing elective primary unilateral THR found a dose-related decrease in VTE events.¹⁵ Patients receiving all edoxaban doses had a statistically lower VTE incidence when compared to patients in the dalteparin control group (dalteparin 10.6% vs edoxaban 15 mg 28.2%, P = .005; 30 mg 21.2%, P < .001; 60 mg 15.2%, P < .001; 90 mg 10.6%, P < .001). Subjects were given the first dose of medication 6 to 8 hours postoperatively, and the medication was continued for 7 to 10 days with bilateral surveillance venography on the last day of study treatment. Again, the majority of VTEs were asymptomatic, with 1 symptomatic pulmonary embolism (PE) in the edoxaban 60 mg group. Incidence of the primary safety outcome was slightly higher in the edoxaban groups, but this did not reach statistical significance (edoxaban 1.6%-2.3% vs dalteparin 0%; P = .583 by Cochran-Armitage test for dose response). No dose–response relationship was found for bleeding outcomes. Four deaths occurred in study participants randomized to the edoxaban arm. Three were determined not to be due to PE on autopsy. PE could not be ruled out as the cause of death in the fourth case as an autopsy was not performed. Post hoc analysis of pharmacokinetic data confirmed a linear relationship between steady-state edoxaban plasma concentrations and efficacy in VTE prevention.¹⁴ Increasing age, male gender, and Eastern European geographic region were found to be associated with increased VTE in this analysis.

A Phase 3 study in 92 subjects enrolled within 10 days of hip fracture surgery (HFS) who were randomized to edoxaban 30 mg daily or enoxaparin 2000 IU (20 mg) twice daily initiated 24 to 36 hours postoperatively and continued for 11 to 14 days found similar rates of VTE and bleeding between groups. Bilateral surveillance venography within 24 hours of study drug completion revealed a 6.5% VTE incidence in the edoxaban group compared to 3.7% in the enoxaparin group (absolute difference 2.8; 95% CI −12.4-14.2).¹⁷ The study was not powered to detect statistical differences in VTE or bleeding rates between the groups. All VTE events were asymptomatic distal DVTs. Incidence of the primary safety outcome was 3.4% in the edoxaban group compared to 6.9% in the enoxaparin group (absolute difference −3.5%; 95% CI −18.8%-6%). One major bleeding event and 1 clinically relevant nonmajor bleed event occurred in each treatment group. Minor bleeding was more common in the edoxaban group (22%) than the enoxaparin group (10.3%). Although overall bleeding rates remained low in this study, incidence of any bleeding event with edoxaban was higher in this study than previously reported. The authors suggested this may have been due to enrollment of patients with lower body weight and lower creatinine clearance (CrCl) than in previous studies.

The largest study to date on the use of edoxaban for VTE is the Hokusai-VTE trial. This multicenter, randomized, double-blind noninferiority trial enrolled 4921 subjects with acute symptomatic DVT and 3319 patients with acute symptomatic PE.¹¹ Subjects were initially treated with unfractionated heparin or enoxaparin for a mean duration of 7 days postenrollment and then randomized to either 60 mg edoxaban daily or warfarin titrated to a target INR of 2 to 3 for 3 to 12 months with duration determined by the treating physician. The dose of edoxaban was reduced to 30 mg daily for patients with CrCl 30 to 50 mL/min, body weight <60 kg, or concurrently on p-glycoprotein (p-gp) inhibitors. Warfarin time in therapeutic range was 63.5%. Edoxaban was shown to be noninferior to warfarin for prevention of recurrent symptomatic VTE at 12 months postenrollment (edoxaban 3.2% vs warfarin 3.5%; P < .001). Significantly lower incidence of the composite primary safety end point occurred in subjects taking edoxaban (8.5%) than those taking warfarin (10.3%; P = .004 for superiority). Rates of VTE and bleeding were similar in subjects who required edoxaban dose adjustments. A subgroup analysis performed on subjects initially enrolled with PE and right ventricular dysfunction, defined as elevated morning N-terminal probrain natriuretic peptide, found lower recurrent symptomatic rates in the edoxaban group than the warfarin group.

Edoxaban was approved in April 2011 for the prevention of VTE following major orthopedic surgery in Japan with a dose of 30 mg once daily (15 mg once daily for patients with CrCL 30-50 mL/min).³⁵ This approval was expanded to the additional indications of stroke prophylaxis in patients with nonvalvular atrial fibrillation and treatment and secondary prophylaxis of VTE and PE in September 2014. Sixty-seven adverse drug reactions in 56 patients were reported in the first 6 months the product was on the market, during which time an estimated 20 000 patients were treated with the medication. The majority of these were bleeding events (51 events in 42 patients), with 15 serious bleeding events involving cerebral (n = 1), gastric (n = 2), and surgical site (n = 12) hemorrhage. Risk factors for serious hemorrhagic events included age ≥75 years and CrCl ≤50 mL/min. Nonserious bleeding events included subcutaneous hemorrhage, wound hemorrhage, postprocedural hematoma, anemia, and hemarthrosis. Adverse events not associated with bleeding were hepatic dysfunction (n = 4) and diarrhea (n = 2). Given that increases in aspartate aminotransferase, alanine aminotransferase, and bilirubin have been noted in some preclinical edoxaban studies, continued monitoring of liver function is prudent.

Betrixaban (PRT-054021)

Betrixaban is another oral direct FXa inhibitor with high specificity toward FXa and a half-life of 20 hours.³⁶ This agent exhibits predominantly biliary excretion and less than 5% of the agent is renally cleared; thus, this negates the need for renal dose adjustments and minimizes the potential for drug interactions due to the lack of cytochrome P450 (CYP) metabolism. Betrixaban does not require any coagulation monitoring and has minimal impact on prothrombin time (PT) and activated clotting time and has only slight elevations in activated partial thromboplastin time (aPTT).

One phase 2 trial has been published evaluating the safety and efficacy of betrixaban. The EXPERT trial was a multicenter, randomized study comparing 2 doses of betrixaban to enoxaparin for VTE prophylaxis after total knee replacement (TKR).³⁶ Subjects were included if they were 18 to 75 years of age, weighing between 50 and 120 kg and undergoing primary unilateral TKR. Major exclusion criteria and additional study details can be found in Table 2. Subjects were randomized to receive betrixaban 15 or 40 mg twice daily or enoxaparin 30 mg twice daily in a 2:2:1 ratio. The first dose of betrixaban was administered 6 to 8 hours postoperatively, while enoxaparin was administered 12 to 24 hours postoperatively for 10 to 14 days. Surveillance venography was performed the day of the final study dose. Patients were followed for 6 weeks postoperatively. Due to the exploratory and descriptive design of this study, formal statistical analyses were not conducted by the researchers.

Of the 214 subjects who received ≥1 dose of study drug, only 175 subjects had evaluable venograms and were included in the primary efficacy and safety analyses. The rate of VTE was lower in the enoxaparin group (10%) than both betrixaban groups (15%-20%). The majority of DVTs were asymptomatic with only 2 symptomatic DVTs, one each in the betrixaban 15 mg and enoxaparin groups. There was also 1 symptomatic PE in each of the betrixaban groups. A PE was also diagnosed on postoperative day 22 in the enoxaparin group. The primary safety end point rates were higher in the enoxaparin group (7%) than either betrixaban group (0%-2.4%). There was only 1 major bleed during the study period, a surgical site bleed in the enoxaparin group. Greater efficacy may be seen with higher doses of betrixaban. Further studies are required to evaluate the optimal dose.

Letaxaban

Letaxaban (TAK-442), another oral FXa inhibitor, has a rapid onset of action, which peaks at 1 to 2 hours. Approximately 30% is renally eliminated, and it has a half-life of 9 to 13 hours.³⁷ This agent was studied in a single, phase 2, randomized, multicenter, dose-ranging trial evaluating the efficacy and safety of TAK-442 compared to enoxaparin for VTE prophylaxis in patients after TKR.³⁷ Subjects were eligible for enrollment if they were ≥18 years of age and undergoing elective primary TKR. Exclusion criteria and study details are listed in Table 2.

Subjects were randomized to 1 of the 7 treatment arms: TAK-442 40 or 80 mg daily, TAK-442 10, 20, 40, or 80 mg twice daily or enoxaparin 30 mg twice daily. TAK-442 was administered 6 to 8 hours postoperatively in a double-blinded fashion with regard to dose and regimen; enoxaparin was administered 12 to 24 hours postoperatively in an open-labeled manner. All treatment medications were administered for at least 10 days. Bilateral surveillance venography was performed at the end of the treatment period.

The primary efficacy end point included all subjects (n = 730) who received at least 1 dose of study medication and had evaluable venograms, while the safety analyses was conducted in an intention-to-treat manner. TAK-442 at doses ranging from 40 to 80 mg daily (23.5% 40 mg daily; 26.8% 80 mg daily) and 40 to 80 mg twice daily (21.4% 40 mg twice daily; P < .001; 14.3% 80 mg twice daily; P < .001) had similar efficacy to enoxaparin 30 mg twice daily (22.0%). The higher rates of VTE with TAK-442 10 and 20 mg twice daily (39% 10 mg twice daily; P = .013; 38.4% 20 mg twice daily; P = .014) groups resulted in early termination of those 2 dosing groups. Similar to other studies, the majority of DVTs were asymptomatic. However, there were 4 symptomatic DVTs in the TAK-442 40 mg twice daily group, 1 in each of the remaining TAK-442 groups, and 2 in the enoxaparin group. One PE was diagnosed in each of the following TAK-442 groups: 10, 20, and 40 mg twice daily. Two PEs occurred in the enoxaparin group. No fatal VTE occurred during the treatment or follow-up period.

There were no differences in the primary safety end point. Rates of major bleeding were as follows in the TAK-442 groups: 0% 10 mg twice daily, 0.8% 20 mg twice daily, 1.2% 40 mg twice daily, 0% 80 mg twice daily, 0% 40 mg daily, 0.6% 80 mg daily versus 1.9% enoxaparin group. The overall rate of adverse events was similar between the TAK-442 groups (94.9%) and the enoxaparin group (90.7%) with the most common adverse events being procedural pain, nausea, constipation, and peripheral edema (Table 2). The rate of treatment discontinuation due to side effects was 2.7% for the TAK-442 groups versus 3.1% for enoxaparin. Twice daily TAK-442 dosing regimens resulted in a statistically significant dose-dependent decrease in the incidence of VTE compared to enoxaparin with no differences in major bleeding rates.

LY517717

LY517717 (LY) is a reversible direct FXa inhibitor, which is primarily eliminated via the gastrointestinal tract.³⁸ LY peaks within 0.5 to 4 hours and has a half-life of 27 hours, allowing for once daily dosing. The absorption of LY can be affected by food; thus, fasting for 1 to 2 hours before and after administration is recommended. A single phase 2 trial has been published evaluating the efficacy and safety of LY compared to enoxaparin for the prevention of VTE after unilateral TKR or THR.³⁸ This study was a multicenter, randomized, double-blind, double-dummy, dose-escalation trial. Subjects were included if they were 18 to 75 years of age, between 50 and 120 kg in weight, and were scheduled for a primary unilateral TKR or THR. Major exclusion criteria can be found in Table 2.

Subjects (n = 131) were initially randomized to 1 of the 4 treatment arms: enoxaparin 40 mg, LY 25, 50, or 75 mg with all administered once daily. Randomization of subjects was stratified based on procedure type. A first interim analysis was conducted and determined that the lower doses were ineffective, defined as a lower bound of the 95% CI >15% set a priori in a per-protocol analysis of the primary efficacy. The lower bound of the 95% CI ranged from 22.0 to 37.1 for all 3 groups; thus, doses of 25 to 75 mg were deemed to be ineffective. An intention-to-treat safety analysis found no significant differences in overall bleeding events, so doses were escalated and new subjects (n = 176) were subsequently randomized to 1 of the 3 treatment arms, that is, enoxaparin 40 mg, LY 100 mg, or 125 mg. After a second interim analysis, dose escalation was again permitted and new subjects (n = 204) were randomized to 4 treatment arms, namely, enoxaparin 40 mg, LY 100, 125, or 150 mg.

All patients were given either LY or matching placebo within 6 to 8 hours of wound closure and then every morning thereafter. Enoxaparin or matching placebo was administered the night prior to surgery and subsequent doses were administered every evening thereafter. The protocol required patients to receive 6 to 10 doses of the study medication with a follow-up visit on study day 30 in order to be included in the primary efficacy analysis. Only a total of 360 subjects were included in the per-protocol efficacy analysis and 507 subjects in the intention-to-treat safety analysis. When comparing incidence of VTE, all LY groups were found to be noninferior to the enoxaparin group (18.8% LY 100 mg, 19.9% LY 125 mg, 15.6% LY 150 mg, and enoxaparin 21.2%; P = .0001). Rates of VTEs were driven by subjects who underwent a TKR. There were no symptomatic DVTs in any study group and only 1 PE was diagnosed on day 21 in the LY 150 mg group.

There were no differences in overall bleeding events among the study groups. Only 1 major bleeding event occurred during the treatment period. This subject was in the LY 100 mg group and developed a thigh hematoma on day 2, which required transfusions. Two major bleeding events occurred during the follow-up period. The first was an intracranial hemorrhage occurring in a patient in the LY 125 mg group on day 28 after a head trauma while receiving enoxaparin for prophylaxis at that time. The other was a surgical site hematoma, which occurred on day 8 in a subject randomized to the enoxaparin arm. There were no deaths related to bleeding in any treatment arm. Additional adverse events are listed in Table 2.

LY at doses of 100, 125, and 150 mg were found to be noninferior to enoxaparin for the prevention of VTEs in TKR and THR with no differences in bleeding. The incidence of VTE decreased in a dose-dependent manner with doses of LY ranging from 100 to 150 mg compared to enoxaparin.

Factor IXa Inhibitors

TTP889

In the coagulation cascade, factor IXa (FIXa) plays an integral role in the intrinsic pathway, especially with the initiation and propagation of coagulation.^39,40 Several parenteral inhibitors of FIXa have been investigated, including agents that inhibit the active site of FIXa,^41,42 monoclonal antibodies directed against FIX/IXa,^42

–46 and synthetic oligonucleotides (RNA aptamers).^47
–49 When compared to heparin, these agents do not appear to have a higher risk of bleeding at therapeutic doses. Partial inhibition of FIXa may offer a new approach with minimal risk of bleeding.⁵⁰ TTP889 is an oral, selective antagonist of FIX/FIXa activity that has been demonstrated to dose dependently inhibit to a maximum of about 90%.⁵¹ The time to peak plasma concentration for TTP889 is 3 hours and the half-life is 21 to 25 hours, which makes once daily dosing feasible. TTP889 has no effect on aPTT, PT, or bleeding time even at supratherapeutic doses.⁵² The study design and outcomes for the study examining TTP889 for VTE treatment are summarized in Table 2.

The anticoagulant potential of TTP889 was investigated in a multicenter, randomized, double-blind study for extended prophylaxis after HFS.⁵² Subjects (n = 261) received either TTP889 300 mg once daily or placebo starting 6 to 10 days after HFS and standard thromboprophylaxis for 5 to 9 days. The first dose of the study medication was given 12 to 48 hours after standard prophylaxis while in the hospital or a rehabilitation facility. The incidence of the primary efficacy outcome was similar between the 2 study groups (32.1% in TTP889 group vs 28.2% in placebo group; P = .58). Eight (7.3%) patients developed symptomatic VTE during treatment. PE was reported for 3 patients with 2 in the TTP889 group (both fatal) and a nonfatal event in the placebo group. Similarly, there was no significant difference in the primary safety outcomes between the groups with no major bleeding events reported.

Reversal Agents for TSOACs

The novel anticoagulants have been developed as alternatives to VKA for the prevention and treatment of VTE and offer more rapid onsets of action, shorter half-lives, less drug interactions, more predictable pharmacokinetics, and without the need for frequent laboratory monitoring. However, these agents lack effective antidotes to reverse the anticoagulant effect in the setting of clinically significant bleeding. Evidence supporting nonspecific hemostatic therapies (such as prothrombin complex concentrate [PCC], activated PCC [aPCC], and recombinant factor VIIa) for reversal is limited to healthy human volunteers, animal models, and in vitro studies.⁵³ In patients receiving a TSOAC, the standard care is to provide supportive care and procedural interventions; clinicians can consider administration of PCC or aPCC in the setting of severe or life-threatening bleeding. There are specific reversal agents that are in development but currently require further investigation. These potential reversal agents include specific FXa antidotes (plasma derived and recombinant Xa derivatives).⁵⁴ A humanized monoclonal antibody fragment against dabigatran is also being developed; in the future, this type of agent may be investigated for other TSOACs.⁵⁵ Adjunctive therapies such as hemodialysis with charcoal hemoperfusion, oral activated charcoal, desmopressin, and antifibrinolytic agents can be considered for management of severe or life-threatening bleeds; however, no studies in human patients receiving TSOAC have demonstrated clinical efficacy.⁵³

Discussion

The oral direct FXa inhibitors have already been extensively studied and have an established role in clinical practice. However, the 3 TSOAC agents on the market (apixaban, rivaroxaban, and dabigatran) require renal dose adjustments and/or twice daily dosing. An agent such as betrixaban has the advantage of not requiring renal dose adjustments, providing a therapeutic option for patients with renal insufficiency.³⁹ However, this agent requires twice daily dosing, which may impact patient compliance. Unfortunately, the result of the EXPERT trial suggests doses of betrixaban studied were not efficacious in preventing VTEs in post-TKR patients compared to enoxaparin. This study was small and exploratory in nature, thus making it difficult to formulate a definitive conclusion on the agent’s efficacy. However, the lack of major bleeding and the higher rates of VTE with betrixaban suggest the need to evaluate efficacy of higher dosing regimens. Further studies are warranted based on these data, including the need for phase 3 studies once optimal doses have been established.

The phase 2 trial evaluating TAK-442 presents promising results for the prevention of VTE post-TKR.⁴⁰ When dosed twice daily, the higher dosing regimens of TAK-442 had significantly lower rates of VTE compared to enoxaparin. However, with lower doses and once daily dosing regimens of TAK-442, there was a higher rate or no difference in the rate of VTE compared to control. Given these results and the relatively short half-life of this agent, future studies evaluating TAK-442 will likely be conducted utilizing a twice daily dosing regimen. TAK-442 also excluded patients with renal insufficiency and therefore does not offer a clear advantage over the currently existing TSOACs. However, having similar rates of bleeding compared to enoxaparin and a reduction in rates of VTE warrants further evaluation.

Unlike betrixaban and TAK-442, LY517717 can be administered both once daily and does not require renal dose adjustments.⁴¹ This provides LY517717 with distinct advantages over rivaroxaban and apixaban. However, this agent’s absorption can be impacted by food and has only been studied during a fasting state. This is a disadvantage of LY517717 when compared to the FDA-approved TSOACs, which do not have significant drug–food interactions. The phase 2 study with LY517717 did support the need for continued evaluation of this agent based on lower VTE rates and similar bleeding rates compared to enoxaparin.

Of the TSOACs currently under investigation, edoxaban has been studied the most thoroughly. The mechanism of action, onset of action, half-life, and bioavailablility of edoxaban are similar FXa inhibitors already approved by the FDA, that is, rivaroxaban and apixaban. Where apixaban is dosed twice daily and only approved for primary VTE prevention, and rivaroxaban requires twice daily dosing for 21 days for initial therapy following VTE when used for treatment and secondary prophylaxis, once daily doses of edoxaban have been studied for both indications. Drug–drug interactions with p-gp inhibitors may occur with coadministration of edoxaban, but significant CYP enzyme interactions are unlikely.

Edoxaban has been studied in humans for a variety of VTE-related indications including primary VTE prophylaxis following TKR, THR, and HFS and treatment and secondary prophylaxis following symptomatic VTE. With the exception of the Hokusai-VTE study, these trials have been underpowered to justify comparison to placebo or active controls.^16,18,34 Enrollment in these studies was also limited to a homogenous patient population. Questions continue to exist regarding appropriate dosing for patients with multiple indications for dose reduction (eg, patient with low body weight on a strong p-gp inhibitor). Further studies in more representative populations are likely needed before widespread use of this agent can be recommended, although the data to date for the indication of acute VTE treatment is similar to other FXa inhibitors that have gained FDA approval.

Edoxaban has not been compared head to head with either rivaroxaban or apixaban. But comparisons of the results from Hokusai-VTE trial to the EINSTEIN-DVT and EINSTEIN-PE trials reveal similar rates of recurrent VTE and bleeding in both the study drug and the comparator groups (EINSTEIN-DVT: rivaroxaban 2.1% recurrent VTE vs 3.0% enoxaparin-VKA; P < .001 for noninferiority; rivaroxaban composite major and clinically relevant nonmajor bleeding 8.1% vs 8.1% enoxaparin-VTE; P = .77; EINSTEIN-PE: rivaroxaban 2.1% recurrent VTE vs 1.8% standard therapy; P = .003 for noninferiority; and rivaroxaban 10.3% composite major and clinically relevant nonmajor bleeding vs 11.4% standard therapy; P = .23).^12,29,30 Of note, while the EINSTEIN trials excluded patients who had received doses of parenteral anticoagulants prior to study enrollment, the Hokusai trial treated patients with parenteral anticoagulants for 7 to 10 days before transition to edoxaban. The study authors explained that this was part of the protocol to encourage maximal enrollment of patients with all grades of VTE. It will be interesting to see if edoxaban is approved for the treatment and secondary prophylaxis of VTE if short-term use of parenteral anticoagulants will be required prior to initiation based on the results of this trial. This study protocol is similar to the RE-COVER trial, which contributed toward the approval of dabigatran for acute VTE after 5 to 10 days of parenteral anticoagulation.⁵⁶

Information on the potential price of edoxaban and how this would compare to the cost of current therapies is not available. Edoxaban, while already approved in Japan, is pending FDA approval as of January 2014.

FIXa inhibitors are a new class of TSOACs, with no comparable FDA-approved agents on the market. The results of the study by Eriksson and colleagues suggest a lack of antithrombotic potential for TTP889 at this dose in the patient population studied.⁵² Also, partial FIXa inhibition with TTP889 may not be adequate in preventing progression of thrombi already present at initiation of therapy. In this study, initiation of therapy occurred 7 days following surgery. Previous data suggest that asymptomatic VTE may be present in approximately 20% of patients at baseline.⁵⁷ The increase in the rate of VTE after 3 weeks of therapy may indicate that TTP889 is ineffective in preventing new thrombus formation when initiated 7 days after surgery. TTP889 inhibits the formation of FIXa and FVIIIa, which is needed to activate FX. By this mechanism, TTP889 is unlikely to inhibit FIX in an existing clot, which may explain the progression of VTE observed in the study.⁵²

Limitations of Studies

Although the included studies offer data on the clinical efficacy and safety of TSOACs for anticoagulation management of VTE, there are several limitations. Many studies excluded patients with important risk factors for bleeding or VTE, poorly controlled hypertension, extreme body weights, and hepatic/renal dysfunction, limiting the applicability to clinical practice. The majority of the studies also compared the TSOACs to parenteral anticoagulants instead of comparable oral agents, which begs the question of their potential role in a market with an expanding number of oral anticoagulants. Also, the definitions of clinical and safety end points were not standardized across studies. For example, some studies limited efficacy outcomes to symptomatic VTEs, where others performed bilateral surveillance venography to identify asymptomatic VTEs. Studies that used surveillance screening may have captured a higher incidence compared to studies that did not. These variations in outcome measures make it challenging to compare findings from each study and assess impact of outcomes determined in the studies on clinical practice.

As most of these were phase 2 studies, they were designed to determine the potential of the agents by evaluating various dosing regimens, rather than focusing on clinical outcomes in representative patient populations with VTE. Thus, these studies had small sample sizes and short follow-up period for monitoring. Further studies are warranted to evaluate the efficacy and safety of each novel anticoagulant in more generalizable patient populations before definitive recommendations for clinical practice can be developed.

Conclusion

The management of VTE has evolved in the last decade, and TSOACs create a new era in anticoagulation. These agents are more convenient because of lower bleeding rates, rapid action on- and offset, wide therapeutic window, predictable dose responsiveness, less interactions with concomitant medications, and minimal laboratory monitoring. Several agents have been FDA approved, including dabigatran, rivaroxaban, and apixaban. However, limitations for use include limited guidance on timing of therapy interruption for surgical procedures, dosing considerations in renal and hepatic impairment, and lack of monitoring for anticoagulation effect at initiation of therapy, long-term efficacy and safety data, and reversal agents in setting of bleeding.

Additional TSOACs are in development to optimize VTE reduction and minimize bleeding risks. Of the agents in development, edoxaban has the most promise due to the robust data supporting its clinical benefit with a similar bleeding risk when compared with TSOACs that are FDA approved. Clinicians should be encouraged to understand TSOACs under investigation, since differences in pharmacokinetics and pharmacodynamics may influence clinical decision making and agent selection for appropriate management of VTE, especially since ability to clinically monitor anticoagulant effect of these agents is lacking. Currently, no direct comparisons between TSOACs have been conducted. Agents under investigation have yet to overcome the major limitations of the currently existing TSOACs. Further studies are necessary to clarify which TSOAC agent is best for the management of VTE in clinical practice.

Footnotes

Addendum

After the submission of this article, Edoxaban (Savaysa^TM) was approved by the FDA in January 2015 for the treatment of VTE and for stroke prevention in patients with atrial fibrillation that is not caused by a heart valve problem.⁵⁸ This agent will be available in three commercially prepared doses, 15 mg, 30 mg and 60 mg beginning in February 2015. The recommended dosing of edoxaban for the treatment of PE or DVT is 60 mg once daily after 5-10 days of parenteral anticoagulation. In patients with renal insufficiency (CrCl 15 to 50 mL/min), those weighing ≤60 kg or on concomitant P-gp inhibitors, the recommended dose is 30 mg once daily. Further studies are likely needed before widespread use of this agent can be recommended.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Kearon

Akl

Comerota

. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e419–e494S.

Hutten

Prins

. Duration of treatment with vitamin K antagonists in symptomatic venous thromboembolism. Cochrane Database Syst Rev. 2006;25(1):CD001367.

Ageno

Gallus

Wittkowsky

. Oral 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):e44–e88S.

Whitlon

Sadowski

Suttie

. Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition. Biochemistry. 1978;17(8):1371–1377.

Wittkowsky

. Warfarin and other coumarin derivatives: pharmacokinetics, pharmacodynamics, and drug interactions. Semin Vasc Med. 2003;3(3):221–230.

Stangier

. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47(5):285–295.

Stangier

Stahle

Rathgen

. Pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor, are not affected by moderate hepatic impairment. J Clin Pharmacol. 2008;48(12):1411–1419.

Kubitza

Becka

Wensing

. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939—an oral, direct factor Xa inhibitor—after multiple dosing in healthy male subjects. Eur J Clin Pharmacol. 2005;61(12):873–880.

Kubitza

Becak

Roth

. Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin. 2008;24(10):2757–2765.

10.

Raghavan

Frost

. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos. 2009;37(1):74–81.

11.

Hokusai-VTE Investigators; Büller

Décousus

Grosso

. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406–1415.

12.

Zahir

Matsushima

Halim

. Edoxaban administration following enoxaparin: a pharmacodynamics, pharmacokinetic, and tolerability assessment in human subjects. Thromb Haemost. 2012;108(1):166–175.

13.

Bathala

Masumoto

Oguma

. Pharmacokinetics, biotransformation, and mass balance of edoxaban, a selective, direct factor Xa inhibitor, in humans. Drug Metab Dispos. 2012;40(12):2250–2255.

14.

Rohatagi

Mendell

Kastrissios

. Characterisation of exposure versus response of edoxaban in patients undergoing total hip replacement surgery. Thromb Haemost. 2012;108(5):887–895.

15.

Raskob

Cohen

Eriksson

. Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement. a randomised double-blind dose-response study. Thromb Haemost. 2010;104(3):642–649.

16.

Mendell

Noveck

Shi

. A randomized trial of the safety, pharmacokinetics and pharmacodynamics of edoxaban, an oral factor Xa inhibitor, following a switch from warfarin. Br J Clin Pharmacol. 2012;75(4):966–978.

17.

Fuji

Fujita

Kawai

. Safety and efficacy of edoxaban in patients undergoing hip fracture surgery. Thromb Res. 2014;133(6):1016–1022.

18.

Ogata

Mendell-Haray

Tachibana

. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol. 2010;50(7):743–753.

19.

Weitz

Eikelboom

Samama

. New antithrombotic drugs: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e120–e51S.

20.

Eriksson

Dahl

Rosencher

. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomized, double-blind, non-inferiority trial. Lancet. 2007;370(9591):949–956.

21.

RE-MOBILIZE Writing Committee, Ginsberg

Davidson

Comp

. Oral thrombin inhibitor dabigatran etexilate vs. North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty. 2009;24(1):1–9.

22.

Eriksson

Dahl

Rosencher

. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost. 2007;5(11):2178–2185.

23.

Schulman

Kearon

Kakkar

. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342–2352.

24.

Schulman

Kearon

Kakkar

. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368(8):709–718.

25.

Turpie

Lassen

Davidson

. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomized trial. Lancet. 2009;373(9676):1673–1680.

26.

Lassen

Ageno

Borris

. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776–2786.

27.

Kakkar

Brenner

Dahl

. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomized controlled trial. Lancet. 2008;372(9632):31–39.

28.

EINSTEIN Investigators; Bauersachs

Berkowitz

Brenner

. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499–2510.

29.

EINSTEIN-PE Investigators, Buller

Prins

Lensin

. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287–1297.

30.

Lassen

Raskob

Gallus

. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomized double-blind trial. Lancet. 2010;375(9717):807–815.

31.

Agnelli

Buller

Cohen

. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368(8):699–708.

32.

Goldhaber

Leizorovics

Kakkar

. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med. 2011;365(23):2167–2177.

33.

Haas

Schellong

. New anticoagulants: from bench to bedside. Haemostaseologie. 2007;27(1):41–47.

34.

Fuji

Fujita

Tachibana

. A dose-ranging study evaluating the oral factor Xa inhibitor edoxaban for the prevention of venous thromboembolism in patients undergoing total knee arthroplasty. J Thromb Haemost. 2010;8(11):2458–2468.

35.

Kuroda

Hirayama

Hotoda

. Postmarketing safety experience with edoxaban in Japan for thromboprophylaxis following major orthopedic surgery. Vasc Health Risk Manag. 2013;9:593–598.

36.

Turpie

AGG

Bauer

Davison

. A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT). Thromb Haemost. 2009;101(1):68–76.

37.

Weitz

Cao

Eriksson

. A dose-finding study with TAK-442, an oral factor Xa inhibitor in patients undergoing elective total knee replacement surgery. Thromb Haemost. 2010;104(6):1150–1157.

38.

Agnelli

Has

Ginsberg

. A phase II study of the oral factor Xa inhibitor LY517717 for the prevention of venous thromboembolism after hip or knee replacement. J Thromb Haemost. 2007;5(4):746–753.

39.

Davie

Fujikawa

. Basic mechanisms in blood coagulation. Annu Rev Biochem. 1975;44:799–829.

40.

Osterud

Rapaport

. Activation of factor IX by the reaction product of tissue factor and factor VII: additional pathway for initiating blood coagulation. Proc Natl Acad Sci USA. 1977;74(12):5260–5264.

41.

Benedict

Ryan

Wolitzky

. Active site-blocked factor IXa prevents intravascular thrombus formation in the coronary vasculature without inhibiting extravascular coagulation in a canine thrombosis model. J Clin Invest. 1991;88:1760–1765.

42.

Spanier

Minanov

. Heparinless cardiopulmonary bypass with active-site blocked factor IXa: a preliminary study on the dog. J Thoracic Cardiovasc Surg. 1998;115(5):1179–1188.

43.

Feuerstein

Patel

Toomey

. Antithrombotic efficacy of a novel murine antihuman factor IX antibody in rats. Arterioscler Thromb Vasc Biol. 1999;19(10):2554–2562.

44.

Toomey

Valocik

Koster

. Inhibition of factor IXa is protective in a rat model of thromboembolic stroke. Stroke. 2002;33(2):578–585.

45.

Spanier

Chen

. Selective anticoagulation with active site-blocked factor IXA suggests separate roles for intrinsic and extrinsic coagulation pathways in cardiopulmonary bypass. J Thorac Cardiovasc Surg. 1998;116(5):860–869.

46.

Refino

Jeet

DeGuzman

. A human antibody that inhibits factor IX/IXa function potently inhibits arterial thrombosis without increasing bleeding. Arterioscler Thromb Vasc Biol. 2002;22(3):517–522.

47.

Rusconi

Scardino

Layzer

. RNA aptamers as reversible antagonists of coagulation factor IXa. Nature. 2002;419(6902):90–94.

48.

Dyke

Steinhubl

Kleiman

. First-in-human experience of an antidote-controlled anticoagulant using RNA aptamer technology: a phase 1a pharmacodynamic evaluation of a drug-antidote pair for the controlled regulation of factor IXa activity. Circulation. 2006;114(23):2490–2497.

49.

Thompson

Chen

. Characterization of factor IX defects in hemophilia B patients. Methods Enzymol. 1993;222:143–169.

50.

Sramek

Kriek

Rosendaal

. Decreased mortality of ischaemic heart disease among carriers of haemophilia. Lancet. 2003;362(9381):351–354.

51.

Ahmad

London

Walsh

. Binding studies of the enzyme (factor IXa) with the cofactor (factor VIIIa) in the assembly of factor X activating complex on the activated platelet surface. J Thromb Haemost. 2003;1(11):2348–2355.

52.

Eriksson

Dahl

Lassen

. Partial factor IXa inhibition with TTP889 for prevention of venous thromboembolism: an exploratory study. J Thromb Haemost. 2008;6(3):457–463.

53.

Siegal

Cuker

. Reversal of novel oral anticoagulants in patients with major bleeding. J Thromb Thrombolysis. 2013;35(3):391–398.

54.

Peng

Hollenbach

. Reconstructed recombinant factor Xa as an antidote to reverse anticoagulation by factor Xa inhibitors. J Thromb Haemost. 2009;17:309.

55.

Van Ryn

Litzenburger

Waterman

. Dabigatran anticoagulant activity is neutralized by an antibody selective to dabigatran in in vitro and in vivo models. J Am Coll Cardiol. 2011;57:E1130.

56.

Schulman

Kearon

Kakkar

. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361(24):2342–2352.

57.

Eriksson

Bauer

Lassen

. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med. 2001;345(18):1298–1304.

58.

Savaysa^TM (edoxaban) [Full prescribing information]. Parsippany, NJ: Daiichi Sankyo, Inc; January 2015.