Abstract
Edoxaban, a direct factor Xa inhibitor, was extensively studied in the prevention and treatment of venous thromboembolism and in patients with nonvalvular atrial fibrillation (AF). The aim of this review is to focus specifically on the efficacy and safety profile of edoxaban in patients with AF from preclinical development through the phase III trial that led to regulatory approval.
Keywords
Edoxaban overview
Edoxaban is an oral, reversible, direct factor Xa inhibitor, with a rapid onset of action, reaching a plasma peak concentration in 1–2 h [Camm and Bounameaux, 2011; Ogata et al. 2010]. Edoxaban has a 62% oral bioavailability, a plasma elimination half life of 10–14 h, and about 50% of it is renally excreted [Lip and Agnelli, 2014]. There are no major effects of food on the pharmacokinetics of edoxaban. As a substrate of the P-glycoprotein transport proteins (P-gp), edoxaban’s concentration is increased with administration of concomitant P-gp inhibitors such as quinidine, verapamil, or dronedarone [Lip and Agnelli, 2014]. Other pharmacokinetic properties and drug–drug interactions are depicted in Table 1. Edoxaban does not require routine laboratory monitoring [Lip and Agnelli, 2014]. Edoxaban plasma concentrations correlate closely with an increase in prothrombin time and international normalized ratio (INR), and to a lesser degree with activated partial thromboplastin time [Lip and Agnelli, 2014]. Measurement of antifactor Xa may also offer a reliable estimation of edoxaban drug concentration [Ruff et al. 2015]. Nevertheless, all of these measurements are subject to a high degree of variability and have not been validated for routine monitoring of edoxaban’s anticoagulant effect.
Pharmacokinetic properties and potential drug–drug interactions of edoxaban.
European Medicines Agency (EMA) label recommends edoxaban 30 mg in concomitant use with dronedarone, erythroycin, ketoconazole, or cyclosporine.
Data are not available.
Concomitant use with rifampicin should be avoided according to the US Food and Drug Administration drug label.
CYP, cytochrome; HIV, human immunodeficiency virus; P-gp, P glycoprotein.
Phase II clinical trials of edoxaban in patients with atrial fibrillation
The key phase II trial of edoxaban treatment in patients with atrial fibrillation (AF) was a randomized, multicenter, parallel group study, in which four doses of edoxaban were compared with warfarin in 1146 patients with AF [Weitz et al. 2010]. The primary outcomes were the occurrence of major or clinically relevant nonmajor bleeding, and elevated hepatic enzymes or bilirubin. Patients were double blinded to edoxaban dose, but open label to warfarin treatment. During 12 weeks of treatment, once daily edoxaban regimens (30 mg, 60 mg) had a safety profile similar to warfarin, and better than the twice daily regimens of edoxaban (30 mg twice daily, 60 mg twice daily). Interestingly, with the same total daily dose of 60 mg, both minimum steady-state concentration and bleeding frequency were higher with the 30 mg twice daily regimen than the 60 mg twice daily regimen (Figure 1). This study was not powered for efficacy, although D-dimer and F1+2 markers of increased activation of coagulation were decreased with edoxaban to a similar extent as with warfarin.
(a) Edoxaban plasma exposure by dosing regimens. (b) Incidence of bleeding events by edoxaban regimens. Adapted with permission from Weitz et al. [2010].
A second phase II trial examined 536 Japanese patients with AF who were randomized to receive double-blinded edoxaban 30, 45, or 60 mg once daily or open-label warfarin (INR 2.0–3.0 for age < 70 years; 1.6–2.6 for age ⩾ 70 years) for 12 weeks [Yamashita et al. 2012]. There were no statistical differences in all bleeding events among the edoxaban groups and no significant differences from the warfarin group. However, a subgroup analysis suggested that low body weight (⩽ 60 kg) was associated with higher rates of major and clinically relevant bleeding events compared with patients greater than 60 kg, in those treated with edoxaban.
Furthermore, in a pharmacokinetic study that included 1281 subjects from phase I and phase II trials with edoxaban, significant increase of the exposure to edoxaban was observed in patients with renal impairment [creatinine clearance by Cockcroft–Gault (CrCl) 30–50 ml/min] and concomitant use of P-gp inhibitors [Salazar et al. 2012]. Finally, an exposure–response analysis found that the incidence of bleeding events increased significantly with increasing edoxaban exposure, and confirmed that the steady-state minimum concentration showed the strongest association with bleeding. Based on these data, two once daily regimens of edoxaban (30 mg, 60 mg), with a dose reduction in specific populations, were selected for investigation in the phase III study.
Phase III clinical trials of edoxaban in patients with AF
ENGAGE AF-TIMI 48 trial
Edoxaban was studied in the phase III Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial [Giugliano et al. 2013]. The ENGAGE AF-TIMI 48 trial was a three-group, randomized, double-blind, double-dummy multinational trial that compared two dosing regimens of edoxaban with warfarin in patients with AF [Ruff et al. 2010]. In brief, eligible patients were 21 years or older who had AF within 12 months prior to randomization, a CHADS2 score of 2 or above, and planned treatment with anticoagulation. Key exclusion criteria included AF due to a reversible cause, CrCl less than 30 ml/min, increased risk of bleeding, recent acute coronary syndrome or stroke within 30 days prior to randomization, and the use of dual antiplatelet therapy or selected potent P-gp inhibitors (e.g. cyclosporine, ketoconazole, clarithromycin). Patients were randomly assigned to receive either edoxaban 60 mg once daily, edoxaban 30 mg once daily, or warfarin (target INR of 2.0–3.0). For patients in either of the edoxaban groups, the dose was halved if one or more of the following characteristics associated with anticipated increased drug exposure were present during randomization or during the study: CrCl 30–50 ml/min, body weight up to 60 kg, or the concomitant use of the P-gp inhibitors verapamil, quinidine, and dronedarone. The standard dose was resumed after randomization if the P-gp inhibitor was discontinued and there was no other reason for dose reduction.
The primary efficacy end point was defined as the composite of stroke (ischemic or hemorrhagic) or systemic embolic event. The principal safety end point was defined as major bleeding during treatment (International Society on Thrombosis and Haemostasis classification) [Schulman and Kearon, 2005]. Other secondary efficacy and safety end points were also examined, as well as several net clinical outcomes that included both efficacy and safety end points.
A total of 21,105 patients were randomized to receive edoxaban 60 mg once daily (higher-dose edoxaban), edoxaban 30 mg once daily (lower-dose edoxaban), or warfarin (median time in therapeutic range 68.4%; IQR 56.5–77.4), and 25% received a reduced dose of edoxaban or matching placebo at randomization (19% due to CrCl 30–50 ml/min). The median age was 72 years (40% were ⩾ 75 years) and 38% were women. The patients had substantial rates of comorbidities, including hypertension (94%), congestive heart failure (57%), and prior stroke or transient ischemic attack (28%). Their mean CHADS2 score was 2.8 ± 1.0 and most of them had permanent or persistent AF (75%).
Efficacy end points
During a median follow up of 2.8 years, the annualized rate of stroke or systemic embolism during the on-treatment period was 1.18% with higher-dose edoxaban [hazard ratio (HR) 0.79; 97.5% confidence interval (CI) 0.63–0.99; p < 0.001 for noninferiority], 1.61% with lower-dose edoxaban (HR 1.07; 97.5% CI 0.87–1.31; p = 0.005 for noninferiority], and 1.50% with warfarin. In the intention-to-treat analysis, there was a trend favoring higher-dose edoxaban versus warfarin (HR 0.87; 97.5% CI 0.73–1.04; p = 0.08) and an unfavorable trend with lower-dose edoxaban versus warfarin (HR 1.13; 97.5% CI 0.96–1.34; p = 0.10). The annualized rates of ischemic stroke were the same with higher-dose edoxaban and warfarin (1.25%/year, p = 0.97), whereas, ischemic stroke was more frequent with lower-dose edoxaban (1.77%/year,p < 0.001 versus warfarin). However, compared with warfarin, both edoxaban regimens significantly reduced hemorrhagic stroke (HR 0.54, 95% CI 0.38–0.77 for higher-dose edoxaban, and HR 0.33, 95% CI 0.22–0.50 for lower-dose edoxaban; p < 0.001 for each), as well as other subtypes of intracranial bleedings [Giugliano et al. 2014]. Compared with warfarin, both doses of edoxaban were associated with lower rates of death from cardiovascular causes (HR 0.86; 95% CI 0.77–0.97; p = 0.013 for higher-dose edoxaban; HR 0.85; 95% CI 0.76–0.96; p = 0.008 for lower-dose edoxaban). The key secondary end point (a composite of stroke, systemic embolism, or death from cardiovascular causes) was reduced with higher-dose edoxaban (HR 0.87; 95% CI 0.78–0.96; p = 0.005) and was not different with lower-dose edoxaban (HR 0.95; 95% CI 0.86–1.05; p = 0.32). Other efficacy end points of the ENGAGE AF-TIMI 48 trial are depicted in Table 2.
Main efficacy and safety data from the ENGAGE AF-TIMI 48 trial.
Efficacy data are from the intention to treat cohort in the ENGAGE AF-TIMI 48 trial. Safety data are from the safety cohort in the ENGAGE AF-TIMI 48 trial.
Adapted with permission from Giugliano et al. [2013].
A 97.5% confidence interval was used.
ENGAGE AF-TIMI 48, Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation Thrombolysis in Myocardial Infarction 48.
Safety end points
Compared with warfarin, treatment with edoxaban was associated with a reduction in bleeding events. The annualized rate of major bleeding was 3.43% with warfarin, 2.75% with higher-dose edoxaban (HR versus warfarin 0.80; 95% CI 0.71–0.91; p < 0.001), and 1.61% with lower-dose edoxaban (HR versus warfarin 0.47; 95% CI 0.41–0.55; p < 0.001). The rates of life-threatening bleeding, and major bleeding plus clinically relevant nonmajor bleeding were 0.78% and 13.02% with warfarin, 0.40% and 11.10% with higher-dose edoxaban, and 0.25% and 7.97% with lower-dose edoxaban, respectively (p < 0.001 for the comparison with warfarin for each dose of edoxaban). The annualized rate of major gastrointestinal bleeding was higher with higher-dose edoxaban than with warfarin (1.51% versus 1.23%, HR 1.23, 95% CI 1.02–1.50), but lower with lower-dose edoxaban (0.82%, HR 0.67, 95% CI 0.53–0.83). Other safety end points of the ENGAGE AF-TIMI 48 trial are depicted in Table 2.
Transition from blinded study drug to open-label anticoagulation
In two prior trials with novel oral anticoagulants (NOACs) [Mahaffey et al. 2013; Granger et al. 2015], there was an excess of both thrombotic and bleeding events in the 30 days after the end of the trial when patients were transitioned from the blinded study drug to open-label antithrombotic therapy. In the ENGAGE AF-TIMI 48 trial, an end of trial transition plan was developed to minimize the excess risks of stroke and bleeding events during this vulnerable period. This plan included selection of the open-label oral anticoagulant [NOAC or vitamin K antagonist (VKA)] by the treating physician and patient, a transition 14-day modified-dose edoxaban for patients randomized to edoxaban (30 mg once daily for patients in whom the edoxaban dose was not reduced before the end of trial visit and 15 mg once daily for patients in whom the edoxaban dose had been reduced before the end of trial visit), early and frequent INR monitoring, and use of a VKA titration algorithm. Of the 13,642 patients who were taking the blinded study drug at the end of trial visit, 68.2% were transitioned to open-label VKA and 31.2% transitioned to an open-label NOAC. In patients transitioned to VKA, 85% of patients had at least one INR greater than or equal to 2.0 by day 14 after the transition and 99% by day 30 [Ruff et al. 2014a]. During the transition phase there were 21 strokes evenly distributed across the three treatment groups (seven strokes in each group). Major bleeding was also similar across the three treatment groups (warfarin 11 events, higher-dose edoxaban 10 events, and lower-dose edoxaban 18 events).
Dose reduction of edoxaban in patients with AF
A prespecified analysis of the ENGAGE AF-TIMI 48 trial examined the relationship between dose reduction, drug concentration, antifactor Xa, efficacy, and bleeding outcomes [Ruff et al. 2015]. In the ENGAGE AF-TIMI 48 trial, 25.3% of the patients (n = 5330) received a reduced dose of edoxaban or matching placebo at randomization, with similar rates in the three treatment groups [Giugliano et al. 2013]. The reasons for dose reduction in the ENGAGE AF-TIMI 48 trial were CrCl of 30–50 ml/min (60%), body weight up to 60 kg (31%), or the concomitant use of the P-gp inhibitors. About 30% of the patients who were dose reduced had more than one reason for dose adjustment. One month after randomization, trough edoxaban concentration was measured in 6780 of the 14,069 patients treated with edoxaban. Dose reduction resulted in a decrease in mean edoxaban concentration of 29% in the higher-dose edoxaban regimen [from 48.5 ng/ml (standard deviation 45.8) to 34.6 ng/ml (30.9)] and 35% in the lower-dose edoxaban regimen [from 24.5 ng/ml (22.7) to 16.0 ng/ml (14.5)]. Edoxaban concentrations and antifactor Xa activity, which was measured in 2865 patients, were highly correlated (r = 0.96, 95% CI 0.95–0.96, p < 0.001). The decreased drug concentration and antifactor Xa activity, as a consequence of dose reduction, did not alter the efficacy of edoxaban compared with warfarin in the prevention of stroke, systemic embolism, or all-cause mortality. However, patients who were dose reduced had an even greater relative reduction in major bleeding with edoxaban compared with warfarin [Ruff et al. 2015]. These results were consistent in patients who were dose reduced due to renal function or low body weight, but not for those who were dose reduced due to the concomitant use of P-gp inhibitors (fewer than 10% of patients), in whom there was a relative increase in the risk of stroke or systemic embolic events with edoxaban relative to warfarin, although the number of events in this group was small.
Subgroups
In subgroup analyses of the primary efficacy end point in the ENGAGE AF-TIMI 48 trial, there were significant treatment interactions according to previous use of VKA, concomitant aspirin use, and concomitant amiodarone use. First, in patients treated with prior VKA (>60 consecutive days), edoxaban demonstrated greater efficacy compared with warfarin in patients who were VKA naive than VKA experienced [O’Donoghue et al. 2015]. Higher-dose edoxaban was superior to warfarin in prevention of stroke or systemic embolism in patients who were VKA naive (HR 0.71, 95% CI 0.56–0.90) and was similar to warfarin in the patients who were VKA experienced (HR 1.01, 95% CI 0.82–1.24; p interaction = 0.028). Lower-dose edoxaban was similar to warfarin for the prevention of stroke or systemic embolism in patients who were VKA naive (HR 0.92, 95% CI 0.73–1.15), but was inferior to warfarin in those who were VKA experienced (HR 1.31, 95% CI 1.08–1.60; p interaction = 0.019).
Second, in patients treated with concurrent aspirin therapy at randomization, both doses of edoxaban were associated with lower rates of stroke or systemic embolism compared with patients not treated with aspirin at baseline (p interaction = 0.06 for higher-dose edoxaban, and p interaction = 0.02 for lower-dose edoxaban). Finally, in the 2492 patients (11.8%) who were receiving amiodarone at randomization in the ENGAGE AF-TIMI 48 trial, stroke or systemic embolism was significantly lower with lower-dose edoxaban versus warfarin compared with patients not receiving amiodarone (HR 0.60, 95% CI 0.36–0.99, and HR 1.20, 95% CI 1.03–1.40, respectively; p interaction < 0.01) [Steffel et al 2015]. This observation might be due to amiodarone’s inhibition of P-gp which resulted in increased levels of edoxaban. No such interaction was observed in patients who received higher-dose edoxaban [Steffel et al 2015].
In the ENGAGE AF-TIMI 48 trial, about 40% of the patients were at least 75 years. In a subgroup analysis that examined the efficacy and safety of edoxaban compared with warfarin in patients under 65, aged 65–74, and at least 75 years old, there was no effect modification of age with the efficacy and safety of edoxaban compared with warfarin (p interaction > 0.05 for the primary efficacy and safety end points) [Kato et al. 2014]. In fact, edoxaban provided a more pronounced relative reduction in major bleeding as age increased, and unlike warfarin, the incidence of intracranial hemorrhage with edoxaban increased only gradually with increasing age. As a result, edoxaban provided superior net clinical benefit over warfarin in older patients [Kato et al. 2014].
A subgroup analysis that examined patients with heart failure in the ENGAGE AF-TIMI 48 trial found that heart failure was independently associated with an increased risk of thromboembolic and bleeding events. The relative efficacy and safety of edoxaban compared with warfarin was consistent in patients with and without heart failure, across the spectrum of heart failure severity, and regardless of the presence or absence of left ventricular systolic dysfunction [Magnani et al. 2014].
Edoxaban and genetics in patients with AF
Patients treated with VKAs have a highly variable response to treatment and thus bleeding is of major concern and a common adverse event [January et al. 2014]. About 40% of the variability of response to warfarin is due to polymorphisms in CYP2C9 and VKORC1 genes, which are involved in warfarin metabolism [Mega et al. 2015]. A large pharmacogenetic study that included 14,348 patients in the ENGAGE AF-TIMI 48 trial found that genetic polymorphism in CYP2C9 and VKORC1 affect the pharmacological and safety outcomes of warfarin therapy. Specifically, patients were genotyped for variants in CYP2C9 and VKORC1, and based on the genetic variants, three groups were created: normal, sensitive, and highly sensitive responders to warfarin [Mega et al 2015]. Compared with normal responders, sensitive and highly sensitive responders were over anticoagulated to a greater proportion of the time in the first 90 days of treatment and had an increased risk of bleeding (sensitive responders HR 1.31, 95% CI 1.05–1.64; p = 0.018; highly sensitive responders HR 2.66, 95% CI 1.69–4.19; p < 0.001). During the first 90 days, treatment with either dose of edoxaban, compared with warfarin, reduced any overt bleeding more in the sensitive and highly sensitive responders than in normal responders (p interaction for higher-dose edoxaban 0.007; p interaction for lower-dose edoxaban 0.004). However, compared with warfarin, bleeding risk with edoxaban was similarly beneficial across the three genotypes after 90 days of treatment. This important study may imply that patients with genetic variants may derive an early differential safety benefit from treatment with edoxaban and perhaps from other direct factor Xa inhibitors or thrombin inhibitors, instead of warfarin.
Reversal agents for edoxaban
Currently, there are no approved specific reversal agents for edoxaban [Crowther and Crowther, 2015]. The first in vivo human study of edoxaban reversal was recently published [Ansell et al. 2014]. This placebo-controlled trial in healthy volunteers examined the addition of PER977, a small synthetic molecule originally developed as a reversal agent for heparin and fondaparinux. The study demonstrated that after a single dose of edoxaban, the blood clotting time improved with the addition of 25 mg of PER977, while 100 mg and 300 mg of PER977 almost completely reversed the effect of edoxaban. The recombinant factor Xa protein andexanet α (PRT4445) may also be a potential reversal agent for edoxaban [Lip and Agnelli, 2014], and a phase II study to assess its safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy volunteers is currently ongoing [ClinicalTrials.gov identifier: NCT01758432].
Nonspecific reversal agents such as prothrombin complex concentrate (PCC), activated PCC, and recombinant activated factor VII were shown to reverse edoxaban anticoagulant activity in ex vivo studies [Crowther and Crowther, 2015; Zahir et al. 2015; Halim et al. 2014]. Both the American and European Practical guidelines suggest the following graded measures in life-threatening bleeding events with factor Xa inhibitors: local hemostasis, fluid replacement, red blood cell transfusion, PCC, activated PCC, and activated factor VII [Heidbuchel et al. 2015; Kovacs et al. 2015].
Cost effectiveness of edoxaban in patients with AF
Several studies have examined the cost effectiveness of edoxaban compared with warfarin in patients with AF, mainly based on models derived from the ENGAGE AF-TIMI 48 data. In the USA, despite higher acquisition costs, edoxaban had a favorable incremental cost-effectiveness profile compared with warfarin in patients with moderate- to high-risk AF [Magnuson et al. 2015]. From an economic perspective, higher-dose edoxaban was found to be better than lower-dose edoxaban, mainly due to higher rate of ischemic stroke with the latter. In addition, edoxaban and apixaban were found to be the most cost-effective NOACs from a German public healthcare insurance perspective, mainly driven by reductions in major bleeding events [Krejczy et al. 2015]. The cost effectiveness of edoxaban versus warfarin was also apparent in a study from a perspective of an Italian health system [Rognoni et al. 2015].
Regulatory approval of edoxaban in patients with AF
In January 2015, the US Food and Drug Administration (FDA) approved the higher-dose edoxaban regimen given once daily for patients with AF at moderate to high risk of stroke and with CrCl 15–95 ml/min (60 mg if CrCl 50–95 ml/min; 30 mg if CrCl 15–50 ml/min) (http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM420704.pdf). The lower-dose edoxaban regimen was not approved by the US FDA due to its inferior protection from ischemic stroke compared with well managed warfarin [Giugliano et al. 2014]. The US FDA approved edoxaban in patients with CrCl up to 95 ml/min based on pharmacokinetic studies which showed that in patients with higher CrCl, edoxaban treatment tended to be less beneficial compared with warfarin in the prevention of ischemic stroke. This may have been related to the lower edoxaban concentrations in patients with better renal function, averaging about 40% less in patients with CrCl greater than 95 ml/min compared with patients with a CrCl of over 50 and up to 80 ml/min. The US FDA label for AF did not recommend dose reduction for patients of low body weight or concomitant use of potent P-gp inhibitors.
In June 2015, edoxaban was approved by the European Medicines Agency Committee for Medicinal Products for Human Use for the prevention of stroke and systemic embolism in patients with nonvalvular AF with one or more risk factors, such as congestive heart failure, hypertension, age at least 75 years, diabetes mellitus, prior stroke or transient ischemic attack (http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002629/WC500186182.pdf). Edoxaban is also approved for use in Japan, Korea, and Switzerland for the prevention of stroke and systemic embolism in patients with AF (http://www.daiichisankyo.com/media_investors/media_relations/press_releases/detail/006189.html), and is pending approval in other countries.
Ongoing clinical trials with edoxaban in patients with AF
The Edoxaban versus Warfarin in Subjects Undergoing Cardioversion of Atrial Fibrillation trial (ENSURE-AF) is a prospective, randomized, open-label clinical trial comparing edoxaban with enoxaparin/warfarin followed by warfarin alone in subjects undergoing planned electrical cardioversion [ClinicalTrials.gov identifier: NCT02072434]. The primary efficacy end point is the composite of stroke, systemic embolic event, myocardial infarction, and cardiovascular mortality, from randomization until the end of follow up (day 56 post cardioversion). The primary safety end point is the composite of major and clinically relevant nonmajor bleeding [Lip et al. 2015]. The Optimizing Antithrombotic Care in Patients with Atrial Fibrillation and Coronary Stents (OAC-ALONE) study [ClinicalTrials.gov identifier: NCT01962545] is an ongoing study aimed to evaluate the efficacy and safety of anticoagulant monotherapy (warfarin or NOAC) compared with anticoagulant in addition to antiplatelet therapy in patients with AF and prior (>12 months) coronary stenting.
Summary and future perspectives
Edoxaban, a once-daily novel factor Xa inhibitor, is the newest of the four NOACs available in clinical practice. It was shown to be at least as effective as well managed warfarin in the prevention of stroke and systemic embolism in patients with AF, and superior to warfarin in reducing bleeding events and cardiovascular death. This translated to a superior net clinical benefit over warfarin in patients with AF. The ENGAGE AF-TIMI 48 trial introduced several new standards in trials with oral anticoagulants, including several dose regimens of the study drug, prespecified dose adjustment for specific circumstances, a planned transition phase between anticoagulants at the end of study, and a genetic substudy (Table 3). Edoxaban treatment offers an excellent alternative to warfarin in patients with AF, and as with other NOACs, addresses some of the limitations associated with the use of VKAs [Holbrook et al. 2005]. NOACs have a more predictable anticoagulant effect, have few drug and food interactions, and there is no need for routine monitoring. Since the NOACs were not prospectively compared with each other in a head-to-head trial [Ruff et al. 2014b], the decision to prescribe one NOAC over the other is mainly based on an individual patient or physician preference, taking into account the existing data regarding availability of different dose regimens and dose adjustments, relative efficacy and safety profile in important patient subgroups, and economic considerations. With the continued surge in NOAC use expected to increase in the coming years [January et al. 2014], research has focused on developing assays for monitoring and reversing the anticoagulant effects of these agents. In addition, vulnerable groups who receive NOACs, such as older people, patients with end-stage renal dysfunction, patients with mechanical heart valves, and patients after percutaneous coronary intervention, should be further evaluated in clinical research.
Summary of secondary analyses from the ENGAGE AF-TIMI 48 trial.
ENGAGE AF-TIMI 48, Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation Thrombolysis in Myocardial Infarction 48; VKA, vitamin K antagonist.
Footnotes
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement
Dr Eisen reports no disclosures. Dr Ruff reports grant support through his institution (Brigham and Women’s Hospital) from Daiichi Sankyo and has served as a consultant and received honoraria from Daiichi Sankyo, Boehringer Ingelheim, Bayer, and Portola; and grant support through his institution outside the submitted work from AstraZeneca, Eisai, Intarcia, and Glaxo Smith Kline.