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Table 1: Completed Phase III trials of edoxaban in the EMA approved indications Trial


Patient population No. of patients


ENGAGE-AF TIMI 48 (NCT00781391)8


AF with moderate-to- high risk of stroke


21,105 Treatment arms


Edoxaban: 30, 60mg 1x/ day Warfarin: dose-adjusted


Main efficacy and safety results Median follow-up: 2.8 years


Non-inferior in stroke and SEE prevention: 1.18%; HR=0.79; 97.5% CI=0.63–0.99; p<0.001 for edoxaban 60mg 1.61%; HR=1.07; 97.5% CI=0.87–1.31; p=0.005 for edoxaban 30mg 1.50% for warfarin Significant major bleeding reduction: 2.75%; HR=0.80; 95% CI=0.71–0.91; p<0.001 for edoxaban 60mg 1.61%; HR=0.47; 95% CI=0.41–0.55; p<0.001 for edoxaban 30mg 3.43% for warfarin


Hokusai-VTE (NCT00986154)9


Acute symptomatic VTE


8292


Edoxaban: 60mg 1x/day Warfarin: dose-adjusted


Non-inferior in recurrent VTE reduction: 3.2%; HR=0.89; 95% CI=0.70–1.13; p<0.001 for edoxaban 3.5% for warfarin


Significant major and non-major bleeding reduction: 8.5%; HR=0.81; 95% CI=0.71–0.94; p=0.004 for edoxaban 10.3% for warfarin


AF: atrial fibrillation; CI: confidence interval; DVT: deep vein thrombosis; HR: hazard ratio; PE: pulmonary embolism; SEE: systemic embolic event; SRI: severe renal impairment; VTE: venous thromboembolism


cutaneous soft tissue haemorrhage (up to 5.9%), epistaxis (up to 4.7%) and vaginal haemorrhage. Bleeding can occur at any site and may be severe and even fatal. Other common adverse reactions for edoxaban were anaemia, rash and abnormal liver function tests.5


Contraindications


Edoxaban is contraindicated in: ● Clinically significant active bleeding ● Hepatic disease associated with coagulopathy and clinically relevant bleeding risk


● Lesions or conditions considered to be a significant risk for major bleeding (for example current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities)


● Uncontrolled severe hypertension ● Concomitant treatment with any other anticoagulants except under specific circumstances of switching oral anticoagulant therapy or when unfractionated heparin is given at doses necessary to maintain an open central venous or arterial catheter


● Pregnancy and breast-feeding.5 Efficacy and safety


28


In a Phase II trial in 1146 AF patients, a once-daily dose of edoxaban 60mg had a lower bleeding frequency than the same daily dose given as BID regimen of 2x30mg. The 60mg QD regimen had significantly fewer major and clinical


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relevant bleedings than warfarin.10 Therefore the QD dosing regimen was further investigated in the following development programme. Two pivotal Phase III studies showed edoxaban’s efficacy and safety in a broad spectrum of thromboembolic manifestations (Table 1).


The ENGAGE AF-TIMI 48 trial,8 involving more than 21,000 patients with NVAF with moderate-to-high risk of stroke, demonstrated that edoxaban was non-inferior to warfarin in preventing stroke or systemic embolism. Edoxaban, at two once-daily dose levels, significantly reduced the risk of haemorrhagic stroke, cardiovascular mortality and major bleeding in the overall study population. Although the risk of major GI bleedings is higher with high dose edoxaban than warfarin, the risk of life-threatening or fatal GI bleeding is similar and the severity and outcomes are no worse than with warfarin.11


Rates of intracranial


haemorrhage were lower for high- and low-dose edoxaban arms compared to warfarin.


Regulatory approval was also granted based on data from the event-driven Hokusai-VTE,9


which confirmed


edoxaban’s non-inferiority to warfarin in reducing the incidence of recurrent VTE in patients with acute symptomatic DVT and/or PE, even among those who discontinued treatment prematurely, and showed significant lower risk of major or non-major bleeding events. Moreover, the risk of recurrence of VTE was lower in a subset of patients with severe PE with evidence of right ventricular dysfunction.9


Edoxaban has been specifically assessed in the context of NVAF associated with renal impairment.


Severely compromised kidney function did not affect the incidence of bleeding events or median PT ratios in a 12-week open-label study conducted in Japan.12


In


a second short-term study, lower doses of edoxaban showed equivalent frequencies of thromboembolic and adverse events and plasma concentrations in patients with NVAF associated with severe renal impairment as in patients with normal renal function or mild impairment treated with a full dose of edoxaban.13 Additionally, in patients with end-stage renal disease, haemodialysis exerted minimal effects on the elimination of edoxaban and no dose adjustments were necessary.14


With the potential to broaden its clinical use, the agent is currently under evaluation in other specific patient populations. The goal of the Hokusai- VTE Cancer trial15


is to compare


edoxaban with dalteparin in the treatment of VTE associated with oncological disease, and the ENSURE-AF trial16


is evaluating the agent’s


prophylactic properties in patients with NVAF undergoing electrical cardioversion. A Phase II trial comparing edoxaban with standard treatment with clopidogrel and aspirin has been conducted in peripheral arterial disease,17 and the results presented at LINC 2016. Efforts to develop either a reversal or


a specific antidote for edoxaban are ongoing. Preclinical studies and studies involving healthy volunteers have yielded promising results. Recombinant human factor VIIa, the factor eight inhibitor bypass activity (FEIBA) and the prothrombin complex concentrate PPSB-HT significantly reduced edoxaban-induced changes in coagulation parameters such as PT and


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