Population pharmacokinetics of edoxaban in patients with symptomatic deep‐vein thrombosis and/or pulmonary embolism—the Hokusai‐VTE phase 3 study

AimsThis study characterized the population pharmacokinetics of edoxaban in patients with symptomatic deep‐vein thrombosis and/or pulmonary embolism in the Hokusai‐VTE phase 3 study. The impact of the protocol‐specified 50% dose reductions applied to patients with body weight ≤ 60 kg, creatinine clearance (CL_cr) of 30 to 50 ml min^–1 or concomitant P‐glycoprotein inhibitor on edoxaban exposure was assessed using simulations.MethodsThe sparse data from Hokusai‐VTE, 9531 concentrations collected from 3707 patients, were pooled with data from 13 phase 1 studies. In the analysis, the covariate relationships used for dose reductions were estimated and differences between healthy subjects and patients as well as additional covariate effects of age, race and gender were explored based on statistical and clinical significance.ResultsA linear two‐compartment model with first order absorption preceded by a lag time best described the data. Allometrically scaled body weight was included on disposition parameters. Apparent clearance was parameterized as non‐renal and renal. The latter increased non‐linearly with increasing CL_cr. Compared with healthy volunteers, inter‐compartmental clearance and the CL_cr covariate effect were different in patients (+64.6% and +274%). Asian patients had a 22.6% increased apparent central volume of distribution. The effect of co‐administration of P‐glycoprotein inhibitors seen in phase 1 could not be confirmed in the phase 3 data. Model‐based simulations revealed lower exposure in dose‐reduced compared with non‐dose‐reduced patients.ConclusionsThe adopted dose‐reduction strategy resulted in reduced exposure compared with non‐dose‐reduced, thereby overcompensating for covariate effects. The clinical impact of these differences on safety and efficacy remains to be evaluated.     

Direct oral anticoagulants and cardiovascular prevention in patients with nonvalvular atrial fibrillation

Introduction: Patients with atrial fibrillation have an increased risk for stroke, systemic embolism and cardiovascular events, including myocardial infarction and cardiovascular death. However, the majority of studies that have analyzed the efficacy of anticoagulants have been focused only on their effects on the risk of stroke.

Areas covered: The available evidence about the association between atrial fibrillation and cardiovascular disease as well as the effects of oral anticoagulation on cardiovascular death and myocardial infarction, with a particular focus on direct oral anticoagulants, was updated in this review.

Expert opinion: The management of patients with atrial fibrillation should not be limited to the prevention of stroke, but should also include the prevention of cardiovascular events. Despite treatment with vitamin K antagonists, many patients with atrial fibrillation still develop cardiovascular complications, particularly individuals whose anticoagulation is difficult to control. Direct oral anticoagulants overcome the majority of limitations of vitamin K antagonists and compared with warfarin, they lead to a greater reduction in the risk of stroke or systemic embolism, all-cause mortality, and intracranial hemorrhage. Although these drugs can only be compared indirectly, it seems that not all direct oral anticoagulants are equal with regard to the prevention of myocardial infarction.     

Edoxaban drug–drug interactions with ketoconazole,erythromycin, and cyclosporine

AimsEdoxaban, a novel factor Xa inhibitor, is a substrate of cytochrome P450 3 A4 (CYP3A4) and the efflux transporter P‐glycoprotein (P‐gp). Three edoxaban drug–drug interaction studies examined the effects of P‐gp inhibitors with varying degrees of CYP3A4 inhibition.MethodsIn each study, healthy subjects received a single oral dose of 60 mg edoxaban with or without an oral dual P‐gp/CYP3A4 inhibitor as follows: ketoconazole 400 mg once daily for 7 days, edoxaban on day 4; erythromycin 500 mg four times daily for 8 days, edoxaban on day 7; or single dose of cyclosporine 500 mg with edoxaban. Serial plasma samples were obtained for pharmacokinetics and pharmacodynamics. Safety was assessed throughout the study.ResultsCoadministration of ketoconazole, erythromycin, or cyclosporine increased edoxaban total exposure by 87%, 85%, and 73%, respectively, and the peak concentration by 89%, 68%, and 74%, respectively, compared with edoxaban alone. The half‐life did not change appreciably. Exposure of M4, the major active edoxaban metabolite, was consistent when edoxaban was administered alone or with ketoconazole and erythromycin. With cyclosporine, M4 total exposure increased by 6.9‐fold and peak exposure by 8.7‐fold, suggesting an additional interaction. Pharmacodynamic effects were reflective of increased edoxaban exposure. No clinically significant adverse events were observed.ConclusionsAdministration of dual inhibitors of P‐gp and CYP3A4 increased edoxaban exposure by less than two‐fold. This effect appears to be primarily due to inhibition of P‐gp. The impact of CYP3A4 inhibition appears to be less pronounced, and its contribution to total clearance appears limited in healthy subjects.     

Randomized,Double-Blind Comparison of Half-Dose Versus Full-Dose Edoxaban in 14,014 Patients With Atrial Fibrillation

BackgroundIn the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial, the lower dose edoxaban regimen (LDER) and the higher dose edoxaban regimen (HDER) were noninferior to well-managed warfarin for stroke prevention in atrial fibrillation.ObjectivesThe objective of the present analysis of the ENGAGE AF TIMI-48 trial was to comprehensively compare the net clinical outcome (NCO) of LDER (30 mg once daily, dose reduced to 15 mg in selective patients) versus HDER (60 mg once daily, dose reduced to 30 mg in selective patients).MethodsThis study performed a pre-specified analysis of the ENGAGE AF-TIMI 48 trial, comparing patients on LDER versus HDER.ResultsThe pre-defined primary NCO (stroke/systemic embolism [SEE], major bleeding, death) was less frequent with LDER (7.26% vs. 8.01%; hazard ratio: 0.90; 95% confidence interval: 0.84 to 0.98; p = 0.014). The secondary (disabling stroke, life-threatening bleeding, or all-cause mortality) and tertiary pre-defined NCOs (stroke, SEE, life-threatening bleeding, or all-cause mortality) were similar between the 2 dosing regimens. Patients randomized to LDER versus HDER had a significantly higher risk of stroke/SEE (2.04% vs. 1.56%; hazard ratio: 1.31; 95% confidence interval: 1.12 to 1.52; p < 0.001). Conversely, major bleeding, intracranial hemorrhage, major gastrointestinal bleeding, and life-threatening bleeding occurred significantly less frequently with LDER compared with those of HDER. These findings were supported by multiple pharmacokinetic findings.ConclusionsIn the ENGAGE AF-TIMI 48 trial, the primary NCO was reduced with LDER versus HDER, whereas the secondary and tertiary NCOs were similar between the 2 dosing regimens. These results may aid physicians in evidence-based individualization of edoxaban dosing. However, the approved HDER remains the standard therapy among the available edoxaban dosing regimens for stroke prevention in atrial fibrillation. (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48 [ENGAGE AF-TIMI 48]; NCT00781391)     

Edoxaban for the prevention of stroke in patients with atrial fibrillation

Introduction: Edoxaban is the last direct oral anticoagulant marketed for the prevention of stroke among patients with nonvalvular atrial fibrillation (AF).

Areas covered: ENGAGE AF–TIMI 48 was the pivotal clinical trial that led to the approval of edoxaban 60 mg once daily. After the publication of this study, a great number of substudies and post hoc analyses have been published, together with some observational studies. The aim of this review was to update the current evidence about the use of edoxaban in AF patients.

Expert opinion: In the ENGAGE AF–TIMI 48 trial, edoxaban 60 mg was noninferior to warfarin for the prevention of stroke or systemic embolism, but significantly reduced the risk of bleeding, major adverse cardiac events and death from cardiovascular causes. The relative efficacy and safety of edoxaban 60 mg compared with warfarin were independent of different clinical conditions, such as prior stroke, age, risk of falls, renal function, hepatic disease, ischemic heart disease, heart failure, valvular heart disease, or cancer. Data about the effectiveness and safety of edoxaban in real-life patients are scarce, but consistent with those of the pivotal clinical trial. Edoxaban seems a cost-effective alternative to warfarin among AF patients with moderate to high thromboembolic risk.     

Pharmacotherapy with oral Xa inhibitors for venous thromboembolism

Introduction: Venous thromboembolism (VTE) causes substantial morbidity and mortality worldwide. The traditional treatment of VTE, with an initial therapy with (low molecular weight) heparin or fondaparinux and a continued treatment with vitamin K antagonists, is effective but has limitations.

Areas covered: The current review summarizes the results of the Phase III trials with the new oral direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban and provides a meta-analysis of these trials in the subgroups of elderly patients (> 75 years) and patients with impaired renal function.

Expert opinion: The practical use of direct Xa inhibitors in the treatment of VTE in general and in specific subgroups is discussed. For elderly patients, patients with extremes of body weight, cancer patients or patients with moderate renal impairment, pooled data suggest that the direct oral Xa inhibitors are a reasonable alternative to standard therapy. For other indications, such as treatment of VTE in children, during pregnancy or in the context of heparin-induced thrombocytopenia, further data from clinical trials are needed.     

Edoxaban for reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation

Introduction: Oral anticoagulation is central to the management of patients with atrial fibrillation (AF) and at least one additional stroke risk factor. For decades, the vitamin K antagonists (e.g. warfarin) remained the only oral anticoagulant available for stroke prevention in AF. The non-vitamin K oral anticoagulants (NOACs) are now available, and these drugs include the direct thrombin inhibitors and factor Xa inhibitors. The latter class includes edoxaban, which has recently been approved for stroke prevention in AF by the United States Food and Drug Administration and the European Medicine Agency. In line with other NOACs, edoxaban avoids the many limitations of warfarin associated with variability of anticoagulation effect and multiple food and drug interactions.

Areas covered: In this review, the currently available evidence on edoxaban in patients with non-valvular AF is discussed. The pharmacology, efficacy and safety, and current aspects of use of edoxaban in patients with non-valvular AF for stroke and thromboembolism prevention are reviewed.

Expert opinion: Phase III trials on edoxaban for stroke prevention in non-valvular AF confirms non-inferiority of edoxaban compared to well-managed warfarin both in terms of efficacy and safety. Currently ongoing and future trials as well as real-world data are warranted to confirm its effectiveness and safety for chronic anticoagulation and improve evidence in other areas which are lacking evidence where NOAC use remains controversial.     

Safety and efficacy of non-vitamin K oral anticoagulants in non-valvular atrial fibrillation: a Bayesian meta-analysis approach

Introduction: Choosing between different non-vitamin K antagonist oral anticoagulants (NOACs) in non-valvular atrial fibrillation (NVAF) is difficult due to the absence of head to head comparative studies. We performed a Bayesian meta-analysis to explore similarities and differences between different NOACs and to rank treatments overall for safety and efficacy outcomes.

Areas covered: Through a systematic literature search we identified randomized controlled Phase III trials of dabigatran, rivaroxaban, apixaban, and edoxaban versus adjusted-dose warfarin in patients with NVAF.

Expert opinion: Warfarin ranked worst for all-cause mortality and intracranial bleedings and had a nil probability of ranking first for any outcome. The risk of major bleeding versus warfarin was lower with apixaban, dabigatran 110 mg, and both doses of edoxaban. All agents reduced the risk of intracranial bleeding versus warfarin. Edoxaban 30 mg was the best among the treatments being compared for major and gastrointestinal bleeding. Dabigatran 150 mg was the best for stroke and systemic embolism. This study suggests that NOACs are generally preferable to warfarin in patients with NVAF. However, safety and efficacy differences do exist among NOACs, which might drive their use in specific subsets of AF patients, allowing prescribers to tailor treatment to distinct patient profiles.     

The laboratory's 2015 perspective on direct oral anticoagulant testing

The introduction of direct oral anticoagulant (DOAC) therapy into clinical use in the past 5 years has had significant impact on the clinical laboratory. Clinicians’ desire to determine plasma drug presence or measure drug concentration, and more recent observations regarding the limitations and utility of coagulation testing in the setting of DOAC treatment, suggest that early published recommendations regarding laboratory testing should be reassessed. These initial recommendations, furthermore, were often based on drug‐spiked plasma studies, rather than samples from patients receiving DOAC therapy. We have demonstrated that reagent sensitivity varies significantly whether drug‐spiked samples or samples from DOAC‐treated patients are tested. Data from drug‐enriched samples must therefore be interpreted with caution or be used as a guide only. We present laboratory assays that can be used to determine drug presence and to measure drug concentration, and provide recommended testing algorithms. As DOAC therapy may significantly impact on specialty coagulation assays, we review those tests with the potential to give false‐positive and false‐negative results.