Clinical trial evaluation: the EDOSURE clinical trial program

Abstract

EDOSURE is a trial program of the direct oral anticoagulant drug edoxaban, comprising ten randomized clinical trials of which eight are currently published. They evaluate the use of edoxaban in the treatment of nonvalvular atrial fibrillation and acute venous thromboembolism, including in special circumstances such as patients undergoing cardiac procedures, cancer-associated venous thromboembolism, and elderly patients whose bleeding risk precludes conventional anticoagulation strategies. As a result of the collective evidence generated by EDOSURE, edoxaban is now recommended as a treatment option by numerous international guidelines. This review summarizes the context, rationale, and key findings of the studies.

Plain language summary

EDOSURE is a collection of clinical trials of the medication edoxaban – a blood thinner used to treat or prevent clotting. It encompasses ten trials, eight of which are complete and two are ongoing. Edoxaban’s main uses are in patients with atrial fibrillation, or venous clots (e.g., deep vein thrombosis). Trials of blood thinners need to assess the balance of effectiveness (how well the drug treats or prevents clotting) against risk (causing bleeding). These trials collectively demonstrate first that edoxaban is an effective treatment in these conditions and is at least as safe as traditional options like warfarin. Second, in patients with atrial fibrillation who are undergoing procedures like cardiac stenting or ablations, edoxaban is as effective as the previous standard treatments. Finally, in higher-risk populations, such as frail and/or elderly patients, edoxaban can represent a relatively safe option at lower doses. This article is a review of the individual trials, their important findings, and potential limiting factors.

Article highlights

• EDOSURE is an ongoing clinical trial program of edoxaban – a direct oral anticoagulant.

• In its entirety, it provides an evidence base for edoxaban use in a variety of clinical scenarios, both for nonvalvular atrial fibrillation (NVAF) and venous thromboembolism (VTE).

• Engage-TIMI-48 (2013) found edoxaban (at two different doses – 30 and 60 mg OD) noninferior to warfarin for the prevention of stroke in patients with NVAF. Edoxaban was safer with regard to bleeding events.

• Hokusai-VTE (2013) assessed edoxaban use in acute VTE. Edoxaban was again noninferior for efficacy (prevention of recurrent VTE), and superior in terms of safety (major or clinically relevant nonmajor bleeding).

• Ensure AF (2016) found that for NVAF patients undergoing direct current cardioversion, both edoxaban and warfarin represent safe anticoagulant strategies, with very low rates of iatrogenic stroke. However, the study was underpowered for the demonstration of noninferiority.

• ELIMINATE-AF (2019) assessed NVAF patients undergoing catheter ablation, with the primary efficacy outcome Similarly to Ensure-AF, rates of stroke and bleeding were very low in both warfarin and vitamin K antagonist arms, precluding noninferiority calculations. The authors concluded, however, both are viable options in this patient group.

• ENTRUST-AF-PCI (2019) examined NVAF patients undergoing percutaneous coronary intervention (PCI), comparing dual therapy with edoxaban + P2Y12 inhibitor, versus triple therapy with warfarin + P2Y12 inhibitor + aspirin. The edoxaban regime was noninferior for efficacy (a composite outcome including stent thrombosis alongside major adverse cardiovascular events), and trended toward superiority for safety (major bleeding).

• ENVISAGE-TAVI AF (2021) investigated edoxaban use after successful transcatheter aortic valve implantation (TAVI) in patients with concomitant AF. The comparator was a vitamin K antagonist (predominantly warfarin). While noninferiority was reached for efficacy, the main finding from this study was a 40% higher risk of bleeding in the edoxaban arm, a potentially surprising contrast to the other trials discussed in this review. One possible explanation for this difference is the older, frailer population undergoing TAVI compared with the other study cohorts.

• Hokusai VTE-Cancer (2017) challenged the idea that heparin-derived anticoagulants were the gold standard in cancer-associated VTE. In this study, edoxaban, met noninferiority thresholds for efficacy and safety compared with dalteparin and trended toward a lower rate of recurrent VTE. There was, however, a signal for increased gastrointestinal bleeding in patients with gastrointestinal malignancies.

• ELDERCARE-AF (2020) was an innovative trial of low-dose edoxaban (15 mg OD) in frail elderly patients who were considered too high risk for traditional anticoagulant medications. Compared with placebo, edoxaban was associated with a 66% reduction in stroke or systemic embolism, at the cost of an increased rate of bleeding, though the latter did not reach statistical significance.

• STABLED and ENRICH-AF are ongoing trials. STABLED is assessing the effect of catheter ablation on stroke risk, in AF patients who are taking edoxaban. ENRICH-AF is investigating edoxaban versus aspirin use in AF patients with recent intracranial hemorrhage and high predicted stroke risk.

• Together – these trials support the use of edoxaban for NVAF and VTE across a broad range of specific clinical scenarios. Its bleeding risk profile is generally favorable compared with warfarin, except possibly in older frailer patients.

Keywords: :

• atrial fibrillation
• edoxaban
• stroke
• venous thromboembolism

Financial disclosure

GYH Lip is a consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, and Anthem. No fees have been personally received. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Data availability

No new data were generated by, nor was the original data of any study analyzed in this work.