Elsevier

American Heart Journal

Volume 160, Issue 4, October 2010, Pages 635-641.e2
American Heart Journal

Trial Design
Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: Design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation–Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF–TIMI 48)

https://doi.org/10.1016/j.ahj.2010.06.042Get rights and content

Background

Vitamin K antagonists have been the standard oral antithrombotic used for more than a half century for prevention and treatment of thromboembolism. Their limitations include multiple food and drug interactions and need for frequent monitoring and dose adjustments. Edoxaban is a selective and direct factor Xa inhibitor that may provide effective, safe, and more convenient anticoagulation.

Study Design

ENGAGE AF–TIMI 48 is a phase 3, randomized, double-blind, double-dummy, multinational, noninferiority design megatrial comparing 2 exposure strategies of edoxaban to warfarin. Approximately 20,500 subjects will be randomized to edoxaban high exposure (60 mg daily, adjusted for drug clearance), edoxaban low exposure (30 mg daily, adjusted for drug clearance), or warfarin titrated to an international normalized ratio of 2.0 to 3.0. The edoxaban strategies provide for dynamic dose reductions in subjects with anticipated increased drug exposure. Blinded treatment is maintained through the use of sham international normalized ratios in patients receiving edoxaban. Eligibility criteria include electrical documentation of atrial fibrillation ≤12 months and a CHADS2 score ≥2. Randomization is stratified by CHADS2 score and anticipated drug exposure. The primary objective is to determine whether edoxaban is noninferior to warfarin for the prevention of stroke and systemic embolism. The primary safety end point is modified International Society on Thrombosis and Haemostasis major bleeding. Recruitment began in November 2008. The expected median follow-up is 24 months.

Conclusions

ENGAGE AF–TIMI 48 is a phase 3 comparison of the novel oral factor Xa inhibitor edoxaban to warfarin for the prevention of thromboembolism in patients with atrial fibrillation.

Section snippets

Study objectives

The primary objective of the ENGAGE AF–TIMI 48 trial is to compare edoxaban to warfarin with regard to the composite primary end point of stroke and systemic embolic events (SEEs).

Study design

ENGAGE AF–TIMI 48 is a large, multinational, randomized (1:1:1), double-blind, double-dummy noninferiority design trial comparing the efficacy and safety of 2 exposure strategies (high and low) of edoxaban to warfarin titrated to an INR of 2.0 to 3.0 (Figure 1). Randomization is stratified by CHADS2 risk score 2 to 3 versus 4 to 6 and factors affecting drug exposure that require edoxaban dose adjustment (see section on drug administration). Enrollment commenced in November 2008 with a projected

Patient population

The study population includes patients with AF at medium or high risk of thromboembolic events (CHADS2 risk score ≥2).16 Eligible subjects include men and women ≥21 years old who have a history of AF of any duration documented by any electrical tracing within the prior 12 months and for which anticoagulation is indicated and planned for the duration of the study. Both VKA-experienced (>60 days of continuous anticoagulation at anytime before randomization) and naive patients are eligible. Key

Study drug administration and maintenance of the double blind

Subjects are randomized through an interactive voice/Web response system (IVRS) (Figure 1). All subjects are dispensed 2 sets of study drug. The first set, edoxaban or matching placebo, is administered as a fixed dose regardless of the INR values. The second set, warfarin or matching placebo, contains different strengths of study drug (1, 2.5, and 5 mg [0.5 mg available in selected countries]) to be adjusted in accordance with INR values to maintain INRs between 2.0 and 3.0, inclusive. Patients

Follow-up procedures

Subjects return for study visits at days 8, 15, and 29 and every month thereafter until the end of the trial (median 24 months anticipated), consistent with current recommendations.18 During follow-up visits, subjects are assessed for adverse events, study end points, INR measured in a blinded fashion, and periodic safety laboratory tests (creatinine, liver function) sent to the central laboratory.

Concomitant medications

All decisions regarding concomitant medications are left to the discretion of the treating physician with a few notable exceptions. If indicated, a single antiplatelet agent is permitted, although the recommended dose of aspirin is <100 mg. If a patient develops an indication for dual-antiplatelet therapy (eg, after coronary artery stent implantation), both study drugs must be temporarily interrupted; and use of open-label VKA is permitted at the physician's discretion. This recommendation is

Study end points

The primary efficacy end point of the trial is the composite of stroke and SEE (online Appendix A). Key secondary end points include, but are not limited to, the composite outcome of stroke, SEE, and cardiovascular mortality or all-cause mortality, as well as each component separately. The TTR (INR 2.0-3.0) will be estimated for each subject randomized to warfarin using the interpolation method of Rosendaal et al.20 The primary safety end point is a modification (adjusts the fall in hemoglobin

Statistical considerations

This is an event-driven study with a goal of collecting a prespecified number of primary efficacy end points occurring on treatment in the modified intent-to-treat (ITT) analysis set that includes all randomized subjects who receive ≥1 dose of randomized study drug. Subjects are considered to be at risk for the primary end point only while taking study drug or during the first 3 days after study drug interruption or discontinuation.

It is hypothesized that ≥1 edoxaban dose exposure will be

Additional scientific investigations

Several additional scientific investigations (Table II) are aimed at improving our understanding of the pathophysiology of AF, providing more accurate predictions of thromboembolic and bleeding risks, and enhancing the assessment of the efficacy of oral anticoagulant therapy in greater detail.

Study organization

The Study Oversight Committee, composed of representatives from the TIMI Study Group, Quintiles (contract research organization), and the sponsor (Daiichi Sankyo Inc), jointly manages all aspects of the trial (online Appendix B). The Steering Committee provides guidance on protocol development, study implementation, conduct of the study, and interpretation of results. An independent data safety monitoring committee is responsible for independent assessment of the study and periodic reviews of

Discussion

There are several promising oral anticoagulants in late-stage clinical development that could replace warfarin for the prevention of stroke in AF. The Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial (N = 18,113) used a prospective, randomized, open-label, blinded-end point design to compare 2 dose strategies of the direct thrombin inhibitor dabigatran (110 and 150 mg twice daily) with open-label warfarin.24 Dabigatran 150 mg twice daily was superior to warfarin in

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