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Review

Edoxaban in the prevention and treatment of thromboembolic complications from a clinical point of view Expert Rev. Cardiovasc. Ther. Early online, 1–14 (2015)

Vivencio Barrios*1 and Carlos Escobar2 1 Department of Cardiology, University Hospital Ramon y Cajal, Alcala University, Madrid, Spain 2 Cardiology Department, University Hospital La Paz, Madrid, Spain *Author for correspondence Tel.: +34 913 368 259 [email protected]

Edoxaban is an oral once-daily factor Xa inhibitor with a predictable anticoagulant effect. After oral administration, edoxaban is rapidly absorbed from the gastrointestinal tract, reaching the peak plasma concentrations at 1–2 h. Oral bioavailability is 62% in healthy subjects and the terminal half-life is approximately 10–14 h. Edoxaban has been extensively studied in three clinical scenarios. In ENGAGE AF-TIMI 48, edoxaban was at least as effective as warfarin, but with a marked lesser risk of bleeding. In the Hokusai-VTE study, edoxaban was as effective as warfarin for the prevention of recurrent venous thromboembolism (VTE) in patients with deep venous thrombosis, pulmonary embolism, or both, but with a lesser risk of bleeding. In the STARS program, edoxaban was more effective for the prevention of VTE after knee or hip arthroplasty than low-dose enoxaparin, without an increased bleeding risk. In this review, the available clinical evidence about edoxaban is updated. KEYWORDS: deep venous thrombosis . direct oral anticoagulants . edoxaban . ENGAGE AF-TIMI 48 . hip arthroplasty . .

Hokusai-VTE . knee arthroplasty . new oral anticoagulants STARS program . venous thromboembolism

Anticoagulation is required in many conditions, including atrial fibrillation (AF), deep venous thrombosis (DVT), or pulmonary embolism (PE), to prevent the development of new-onset or recurrent thromboembolic complications. AF is the most common tachyarrhythmia in clinical practice, particularly in elderly patients [1]. Untreated AF doubles the risk of heart-related death and causes a fivefold increased risk for stroke [2]. In addition, strokes related to AF are associated with higher mortality, disability, and recurrence risk [3,4]. Less than 20% of patients with AF have lone AF. In fact, the great majority of patients with AF have one or more comorbidities that increase the risk of stroke [5]. Thus, in the AnTicoagulation and Risk Factors In Atrial Fibrillation (ATRIA) study, nearly 50% of patients were hypertensives, approximately one-third had coronary heart disease, about 30% heart failure, 17% diabetes mellitus, and 9% ischemic stroke [6]. In caracterizacion y

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10.1586/14779072.2015.1053871

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non-valvular atrial fibrillation

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pulmonary embolism

eVALuacion de los pacientes con Fibrilacion Auricular atendidos en consultas de Atencion Primaria (VAL-FAAP) study, 93% of patients had hypertension, 21% coronary heart disease, 21% heart failure, 34% diabetes, and 11% previous cerebrovascular disease. Consequently, more than two-thirds of patients assisted in primary care have a cardiac failure, hypertension, age, diabetes, stroke [doubled] (CHADS2) score ‡2, and nearly 86% a CHA2DS2VASc (cardiac failure, hypertension, age ‡75 [doubled], diabetes, stroke [doubled]-vascular disease, age 65–74 years, and sex category [female]) score ‡2 [1,7]. This means that the great majority of patients with AF should be anticoagulated to prevent stroke, transient ischemic attack, or pulmonary embolism. In fact, effective anticoagulation is associated not only with stroke prevention but also with a reduction in the severity of stroke and with an improvement of functional outcome and survival [4].

 2015 Informa UK Ltd

ISSN 1477-9072

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Review

Barrios & Escobar

Without adequate antithrombotic treatment, DVT and PE may occur after total hip or knee replacement surgery. In fact, PE is the leading cause of preventable hospital death. Several clinical trials have shown that appropriate prophylaxis to prevent venous thromboembolism (VTE) is safe and effective in both surgical and medical patients. As a result, it is recommended that except in the case of contraindication, patients should receive anticoagulant prophylaxis (i.e., low-molecular-weight heparin, fondaparinux, vitamin-K antagonist or approved oral direct anticoagulants) for a minimum period of 10 days after surgery. The duration of prophylaxis should be individualized according to the risk of thrombotic event and bleeding [8–11]. VTE is the third most common cardiovascular disease after myocardial infarction and stroke. It has been estimated that the annual incidence of acute VTE is around one to two cases per 1000 persons in the overall population [12]. Appropriate treatment during the first 6–12 months significantly reduces the risk of recurrence, but the risk of recurrence remains during the first year after treatment is interrupted [13,14]. Traditionally, the standard treatment consisted of low-molecular-weight heparin followed by vitamin K antagonists [15]. However, recent clinical trials have shown that new oral direct anticoagulants may be an appropriate alternative to the traditional approach [16–19]. Traditional therapies have many limitations. Low-molecularweight heparins and fondaparinux require subcutaneous administration. This may be a disadvantage compared with oral anticoagulants. Moreover, transition to vitamin K antagonists may be difficult in some patients, and depending on individuals, may increase the risk of either thromboembolic or bleeding events (i.e., although the therapeutic doses of low-molecular-weight heparins in patients not taking vitamin K antagonists are well known, it seems more difficult to ascertain the exact dose of lowmolecular-weight heparins when patients are taking vitamin K antagonists and they have not reached the INR target yet) [15,17]. Vitamin K antagonists have important limitations that include narrow therapeutic window, highly variable metabolism, existence of multiple interactions with other drugs and food, and slow onset and ending of action. As a result, frequent monitoring of anticoagulant activity and continuous dose adjustments are required [20,21]. Moreover, it has been reported that in patients with non-valvular AF (NVAF) and a CHADS2 score ‡2, those individuals with an INR control over 70% of time in therapeutic range experienced a significant beneficial effect on stroke prevention [22]. Unfortunately, among patients with NVAF taking vitamin K antagonists, around 40–50% of INR values are outside [23,24]. In addition, due to the limitations of vitamin K antagonists, many patients with a clear indication of anticoagulation do not receive the appropriate treatment [1,25]. New direct oral anticoagulants do not have a narrow therapeutic window, and exhibit a predictable anticoagulant effect, and few interactions with other drugs or food. Consequently, no periodic monitoring of coagulation is required, and fixed dose therapy can be taken [20,21]. Edoxaban is a once-daily oral anticoagulant that rapidly and selectively inhibits factor Xa in a concentration-dependent way. Edoxaban has an extensive doi: 10.1586/14779072.2015.1053871

clinical development program, with particular focus on NVAF and VTE [26]. In this review, the available evidence about edoxaban is updated from a clinical point of view. Pharmacokinetics of edoxaban

Edoxaban is an oral and reversible direct factor Xa inhibitor. This inhibition provides a potent anticoagulant effect. Importantly, edoxaban has a predictable dose-dependent anticoagulation effect [27]. After oral administration, edoxaban is rapidly absorbed from the gastrointestinal tract, reaching the peak plasma concentrations at 1–2 h. Oral bioavailability of edoxaban is 62% in healthy subjects and the terminal half-life of edoxaban is approximately 10–14 h [26–29]. Plasma protein binding of edoxaban ranges 40–59%. All these data are not significantly modified by food intake, ethnicity, age or gender [26,30]. Exposure of edoxaban may increase in patients £60 kg, and a 50% dose reduction of edoxaban may be required. Importantly, the label recommendations performed in USA indicate this reduction only in case of treatment for DVT and PE, but not for NVAF patients (TABLE 1) [26,31]. Peak anti-factor Xa activity is achieved approximately 1.5 h after oral intake. However, anti-factor Xa activity lasts for up to 24 h [26,32]. But more importantly, it has been observed that bleeding related with edoxaban is more closely correlated with minimum concentration levels of the drug (trough levels) than with total exposure or maximum concentration levels [33]. The doses used in the three major Phase III trials performed with edoxaban were based on Phase II trials that studied PK/PD [29]. A study compared the safety of four fixed-dose regimens of edoxaban (30 mg q.d., 30 mg b.i.d., 60 mg q.d., or 60 mg b.i.d.) with warfarin in 1146 patients with NVAF during a 12-week follow-up; whereas major plus clinically relevant nonmajor bleeding occurred in 3.2% of patients randomized to warfarin, the incidence of bleeding was significantly higher with the edoxaban 60 mg b.i.d. (10.6%; p = 0.002) and 30 mg b.i.d. regimens (7.8%; p = 0.029), but not with the edoxaban 60 mg q.d. (3.8%) or 30 mg q.d. regimens (3.0%). This could be related with the fact that for the same total daily dose of 60 mg, trough edoxaban concentrations were higher when edoxaban was taken twice daily than when it was taken once daily [34]. Similarly, a recent population pharmacokinetic/ pharmacodynamic (PK/PD) modeling analysis showed that the more prolonged suppression of factor Xa over the dosing interval for a 30 mg b.i.d. dose compared with a 60 mg once-daily dose may explain the significantly higher bleeding rate with the former dose [35]. In addition, higher rates of bleeding have also been reported with the twice-daily versus once-daily dosing of darexaban, an oral direct Xa inhibitor, in a phase II study in patients with an acute coronary syndrome [36]. All these data justify that edoxaban should be administered only once daily in patients with NVAF, and not twice daily as is the case for other direct anticoagulants. Of note, edoxaban is the only once-daily oral direct anticoagulant specifically tested in Phase II clinical trials to find the most appropriate dose in AF patients. Expert Rev. Cardiovasc. Ther.

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Edoxaban from a clinical point of view

Review

Over 70% of edoxaban is excreted Table 1. Pharmacokinetics of edoxaban. unchanged. Less than 4% is metabolized Parameter Value by cytochrome P450, but intestinal Mechanism of action Factor Xa inhibition transport of edoxaban occurs through P-glycoprotein (P-gp) [26,37]. Edoxaban is Prodrug No eliminated in feces and urine, but only Frequency of administration Once daily 35% of edoxaban is eliminated via the Bioavailability 62% kidneys (more recent studies suggest that renal elimination of edoxaban is up to Time to maximum 1–2 h 50%) [26–28,38]. As a result, relevant P-gp plasma concentration inhibitors may have an important effect Plasma protein binding 40–59% on edoxaban concentrations. Thus, quiniTerminal half-life 10–14 h dine, verapamil, and dronedarone increase edoxaban exposure by nearly 77, Renal elimination 35–50% 53, and 85%, respectively. Consequently, Cytochrome P450 metabolism Minimal (