Edoxaban (Fig. 3.4) is a potent, highly selective factor Xa inhibitor with a high affinity for free factor Xa (Ki 0.56 nM) and for factor Xa bound to the prothrombinase complex (Ki 2.98 nM) . It has predictable and consistent pharmacokinetics with dose proportional increases in plasma concentrations, and a half-life of approximately 10–14 h [10, 41, 42]. Additionally, edoxaban has a rapid onset of action and high oral bioavailability (61.8 %), reaching maximum plasma concentrations 1–2 h after administration, and inhibition of thrombin formation over ~24 h, supporting once-daily dosing [10, 12, 43]. Moreover, edoxaban is mainly metabolized via hydrolysis, whereas CYP450 enzymes play an insignificant role.
Around 35 % of the given dose is eliminated via the kidneys , indicating the importance of the kidneys in the excretion of edoxaban. Consequently, studies have evaluated edoxaban in patients with renal impairment and suggest that in patients with chronic kidney disease, edoxaban exposure is increased and a lower dose is appropriate .
The pharmacokinetics of edoxaban are not influenced by gender, age, ethnicity, or food intake, although small but clinically insignificant changes in pharmacokinetics after a high fat meal or in the elderly is observed [10, 46]. Edoxaban has minimal drug interactions, however like all factor Xa inhibitors, edoxaban is a substrate of P-glycoprotein (P-gp) and therefore has potential for interaction with strong P-gp inhibitors. As such, a 50 % dose reduction to edoxaban 30 mg is recommended when concomitantly used with the P-gp inhibitors, ciclosporin, dronedarone, erythromycin, or ketoconazole. In contrast no dose adjustment is necessary with amiodarone, quinidine or verapamil . The predicable pharmacokinetic and pharmacodynamics profiles of edoxaban allows for its use without regular laboratory monitoring .
Similar to other factor Xa inhibitors, currently there is no antidote for edoxaban. However a recently completed phase I study evaluated the effects of PER977 on bleeding following administration of edoxaban to healthy subjects (clinicaltrials.gov identifier NCT01826266) . PER977 was found to be effective in restoring baseline hemostasis 10–30 min after administration of 100–300 mg PER977, this effect was sustained for 24 h . An additional phase II study is underway investigating the re-anticoagulation effect of edoxaban following reversal by PER977 (clinicaltrials.gov identifier NCT02207257) . This trial also aims to identify a dose regimen of PER977 that is able to reverse the effects of edoxaban for 21 h.
Edoxaban was approved in Japan for prevention of VTE following lower-limb orthopedic surgery and in the US for the prevention of stroke and systemic embolic events (SEE) in NVAF and for the treatment of PE and DVT and prevention of recurrent VTE . Edoxaban received European approval in June 2015 following a positive opinion from the CHMP for the use of edoxaban for the prevention of AF related stroke and treatment of PE and DVT and prevention of recurrent VTE . The clinical development of edoxaban can be seen in Table 3.8.
3.3.1 Venous Thromboembolism Prevention in Major Orthopedic Surgery
Two phase II dose-finding studies, 011  and J04 , investigated the use of edoxaban for the prevention of VTE after joint replacement. Study J04 was a placebo controlled study that evaluated edoxaban 5, 15, 30, or 60 mg qd for prevention of VTE following TKR in Japanese patients . Patients were treated for 11–14 days following surgery. There was a significant, dose-dependent reduction in the incidence of VTE with edoxaban compared with placebo, with a comparable risk of bleeding across all treatment groups with no significant differences among edoxaban doses or between edoxaban and placebo.
In the double-blind, active-controlled, multicenter 011 study, 903 patients were randomized to receive oral edoxaban (15, 30, 60, or 90 mg od) or subcutaneous dalteparin qd (initial dose 2500 IU, subsequent doses 5000 IU) . Both medications were started 6–8 h after surgery and administered for 7–10 days. Data from 776 participants were included into the primary efficacy analysis. The primary efficacy endpoint of total VTE was significantly lower in subjects treated with edoxaban (28.2 %, 21.2 %, 15.2 %, and 10.6 % for edoxaban 15, 30, 60, and 90 mg, respectively) than in those receiving dalteparin (43.8 %, P < 0.005) (Table 3.9).
The open-label STARS J-IV  trial investigated the safety and efficacy of edoxaban in preventing VTE after major joint surgery in 92 Japanese patients undergoing hip fracture surgery. Patients were randomized to either edoxaban 30 mg qd (6–24 h post-surgery) or enoxaparin 2000 IU bid (24–36 h after surgery). The primary endpoints were bleeding events and secondary events included thromboembolic events and adverse events. STARS J-IV found that treatment with edoxaban was as safe and efficacious as enoxaparin treatment, and major or CRNM bleeding occurred less often in the edoxaban group compared with the enoxaparin group (3.4 % and 6.9 % respectively). However, thromboembolic events occurred more often in the edoxaban group (6.5 % vs 3.7 %) (Table 3.9).
Two pivotal, randomized, double-blind, multicenter, phase III trials compared edoxaban 30 mg qd to enoxaparin in knee surgery, STARS E-III , and hip surgery, STARS J-V . In both STARS E-III and STARS J-V edoxaban 30 mg qd was superior to enoxaparin in the preventions of VTE, with comparable rates of bleeding [55, 57]. Supported by the data from these phase III studies edoxaban was approved in Japan in April 2011 for the prevention of VTE following lower-limb orthopedic surgery.
A post-marketing vigilance report  recorded all spontaneously reported adverse drug reactions (ADR) that occurred following the launch of edoxaban in Japan, from July 2011 to January 2012. During this time approximately 20,000 patients had been treated with edoxaban. A total of 67 ADR were reported in 57 patients, the majority of ADR were bleeding events, 15 of which were serious. Most ADR occurred in the first week of treatment and none were fatal. The post-marketing analysis found that in the real-life setting the safety profile of edoxaban was consistent with that found in clinical trials and no unforeseen safety signals were observed.
3.3.2 Stroke Prevention in Atrial Fibrillation
In a parallel-group, active controlled phase II study the safety of four fixed-dose regimens of edoxaban were compared with warfarin in 1146 patients with NVAF. Patients were randomized to edoxaban 30 mg od, 60 mg od, 30 mg bid, 60 mg bid, or warfarin (INR 2.0–3.0) . A significantly higher incidence of major and/or CRNM bleeding was seen in the twice-daily edoxaban regimen (60 mg bid, 10.6 %, P = 0.002; 30 mg bid, 7.8 %, P = 0.029) than warfarin (3.2 %), however there were no significant differences between the warfarin and once-daily regimens. For the same total daily dose of edoxaban, 60 mg, the 30 mg bid dose was associated with a trend towards an increase in major bleeding plus CRNM bleeding compared with 60 mg qd (P = 0.08). This study concluded that treatment with edoxaban 30 or 60 mg qd was safe and well tolerated.
A pooled pharmacokinetic analysis  was performed on data from 15 phase I and II studies which aimed to characterize edoxaban population pharmacokinetics. Using an exposure-response analysis (in which Cmin was the best predictor of bleed probability), a 50 % dose reduction in selected patients was recommended, especially in patients with renal impairment, concomitant use of P-gp inhibitors, and body weight ≤60 kg. Consequently, two doses of edoxaban (30 mg and 60 mg od) were selected for investigation in the phase III ENGAGE AF-TIMI 48 trial.
The ENGAGE AF-TIMI 48 study  investigated the safety and efficacy of two doses of edoxaban compared with warfarin. A total 21,105 patients with a history of AF were enrolled into the study making this the largest study of a NOAC in patients with AF to date. Patients were randomized to edoxaban 60 mg qd (n = 7012), edoxaban 30 mg qd (n = 7002) or warfarin (n = 7012; median time in therapeutic range, 68.4 %). In the edoxaban group, patients with moderate renal impairment (creatinine clearance [CrCl] 30–50 mL/min), weight ≤60 kg or who were receiving select P-gp inhibitors had a 50 % dose reduction. Median follow-up duration was 2.8 years. The primary efficacy objective was the non-inferiority of edoxaban compared with warfarin in the prevention of stroke and SEE, key secondary outcomes included a composite of stroke, SEE or death from CV causes, major adverse cardiac events (MACE), and stroke, SEE or death . The primary safety outcome was major bleeding during treatment. The primary efficacy endpoint occurred in 232 patients treated with warfarin (1.50 %/y), 182 patients treated with edoxaban 60 mg qd (1.18 %/y; HR vs warfarin 0.79, 95 % CI 0.63–0.99; P < 0.001 for non-inferiority), and 253 patients treated with edoxaban 30 mg qd (1.61 %/y; HR vs warfarin 1.07. 95 % CI 0.87–1.31; P = 0.005 for non-inferiority). Additionally, ENGAGE AF-TIMI 48 met the pre-specified criteria for non-inferiority and both doses were compared with warfarin in a test for superiority. For patients treated with warfarin the annualized rate of the primary endpoint was 1.80 % compared with 1.57 % in the edoxaban 60 mg qd group (HR 0.87, CI 0.73–1.08; P = 0.08), and 2.04 % in the edoxaban 30 mg qd group (HR 1.13, CI 0.96–1.34; P = 0.10) (Fig. 3.5) .
The primary safety endpoint of major bleeding occurred in 524 patients in the warfarin group (3.43 %/y), compared with 418 patients in the edoxaban 60 mg qd group (2.75 %/y; HR 0.80; 95 % CI, 0.71–0.91; P < 0.001), and 254 patients in the edoxaban 30 mg qd group (1.61 %/y; HR, 0.47; 95 % CI, 0.41–0.55; P < 0.001) (Fig. 3.6) . The rates of all three pre-specified secondary outcomes were significantly lower with edoxaban 60 mg than with warfarin.
Based on the findings from ENGAGE AF-TIMI 48, edoxaban 60 mg was approved by the FDA in January 2015 for the prevention of stroke and SEE in NVAF. According to the label given by the FDA edoxaban 60 mg dose should be reduced to 30 mg in patients with a CrCl 15–30 mL/min and should not be used in patients with CrCl >95 mL/min due to increased risk of ischemic stroke compared with warfarin. In ENGAGE AF-TIMI 48, 77 % of patients had a CrCl <95 mL/min . Additionally, edoxaban received European approval following a positive opinion from the CHMP for the use of edoxaban in Europe in patients with NVAF, which did not include a limitation according to renal function . Edoxaban has also been approved in Japan and Switzerland for prevention of ischemic stroke and systemic embolism in patients with AF.
3.3.3 Treatment of Venous Thromboembolism
The phase III, event-driven, randomized, double-blind, double-dummy, parallel-group, multinational study Hokusai-VTE [61, 62] investigated the safety and efficacy of edoxaban in prevention of VTE. The design of Hokusai-VTE aimed to broaden the applicability of edoxaban use in VTE treatment to real world practice, and encourage enrolment of a broad type of patients, including those with extensive disease . Hokusai-VTE allowed for variable treatment duration from 3 to 12 months, regardless of treatment duration all patients were observed for 12 months .
A total of 8292 patients were randomized to receive open-label heparin (for ≥5 days) followed by either edoxaban 60 mg qd (started after discontinuation of heparin) or warfarin (started concurrently with heparin and until INR 2.0–3.0). A 50 % dose adjustment occurred in the edoxaban group at randomization and any point during the study in patients with moderate renal impairment (CrCl 30–50 mL/min), weight ≤60 kg or who were receiving select P-gp inhibitors. Hokusai-VTE was unique in that dose adjustment not only occurred at randomization but could occur at any point during the study as necessary. Additionally, the flexible treatment duration is unique to Hokusai-VTE, which is unusual in clinical trials but is more in line with clinical practice. The primary efficacy endpoint was symptomatic recurrent VTE during the 12 month study period and the objective of the study was to determine the non-inferiority of heparin follow by edoxaban compared with heparin followed by warfarin. The secondary endpoints included a composite of symptomatic recurrent DVT, non-fatal symptomatic recurrent PE and all-cause mortality, and a composite clinical outcome of symptomatic recurrent DVT, non-fatal symptomatic recurrent PE, and CV mortality. The primary safety endpoint was major or CRNM bleeding, secondary endpoints included all deaths, major adverse cardiovascular events, liver enzyme and bilirubin abnormalities. Over the 12 month study period edoxaban was found to be non-inferior to warfarin for the primary outcomes; symptomatic recurrent VTE occurred in 3.2 % of patients in the edoxaban group and 3.5 % of patients in the warfarin group (HR 0.89; 95 % CI, 0.70–1.13; P < 0.001 for non-inferiority) (Fig. 3.7).
Additionally, Hokusai-VTE analyzed events that occurred on-treatment. Symptomatic recurrent VTE occurred in 1.6 % of the edoxaban group and 1.9 % of the warfarin group (HR, 0.82; 95 % CI, 0.60–1.14; P < 0.001 for non-inferiority). In a pre-specified analysis of patients that required dose adjustment edoxaban was also found to be non-inferior to warfarin, with events occurring in 3.0 % and 4.2 %, respectively (HR, 0.73; 05 % CI, 0.42–1.26). In the subgroup of patients with PE and evidence of right ventricular dysfunction (N-terminal-prohormone of brain natriuretic peptide level of ≥500 pg/mL), recurrent VTE occurred in 3.3 % of patients (15/454) in the edoxaban group and in 6.2 % of patients (30/484) in the warfarin group (HR, 0.52; 95 % CI, 0.28–0.98). Similar results were observed among patients with right ventricular dysfunction as assessed by means of computed tomography (HR, 0.42; 95 % CI, 0.15–1.20). During the 12 month study period the primary safety outcome occurred in 8.5 % of the edoxaban group and 10.3 % of the warfarin group (HR, 0.81; 95 % CI, 0.71–0.94; P = 0.004 for superiority) demonstrating that edoxaban caused significantly less bleeding than warfarin (Fig. 3.8).
In the pre-specified analyses of the dose adjusted edoxaban patients first major or CRNM bleeding occurred in 7.9 % of edoxaban patients and 12.8 % of warfarin patents (HR, 0.62; 95 % CI, 0.44–0.86).
In January 2015, based on the results from Hokusai-VTE, edoxaban 60 mg was approved in the US for the treatment of DVT and PE following 5–10 days parenteral heparin. In patients with CrCl 30–50 mL/min, body weight ≤60 kg and patients receiving concomitant P-gp inhibitors edoxaban 60 mg should be reduced to 30 mg . Additionally, based on data from Hokusai-VTE edoxaban was recommended by the CHMP for the treatment of DVT and PE and prevention of recurrent PE and DVT in adults . Edoxaban has also been approved in Japan and Switzerland for VTE treatment and secondary prevention.