ELIMINATE-AF: Edoxaban Viable Alternative to VKA in AF Ablation

Daniel M. Keller, PhD

April 03, 2019

LISBON — Uninterrupted, once-daily edoxaban (Savaysa, Daiichi Sankyo) compared favorably with uninterrupted vitamin K antagonists (VKAs) in terms of efficacy and safety during and after catheter ablation in patients with atrial fibrillation (AF), an exploratory study shows.

Although edoxaban has proven safe and efficacious for preventing strokes in patients with AF, data have been lacking for its use during ablation. Therefore, the blinded, prospective, randomized, open-label, phase 3b Evaluation of Edoxaban Compared With VKA in Subjects Undergoing Catheter Ablation of Non-valvular Atrial Fibrillation (ELIMINATE-AF) trial was designed to descriptively compare edoxaban with VKAs on the composite efficacy end point of all-cause death, any form of stroke, and major bleeding by the International Society on Thrombosis and Hemostasis (ISTH) definition.

"ELIMINATE-AF shows that an uninterrupted anticoagulation regimen with edoxaban 60 mg QD in patients undergoing AF catheter ablation results in low rates for both thromboembolic and bleeding events," Stefan Hohnloser, MD, professor of medicine and cardiology, Johann Wolfgang Goethe University, Frankfurt, Germany, told delegates here at the European Heart Rhythm Association 2019 Congress.

Patients in the study (n = 560) were randomized 2:1 to edoxaban 60 mg daily (or 30 mg according to dose-reduction criteria) or a VKA, respectively, for at least 21 days. They then underwent transesophageal echocardiography, catheter ablation, and MRI and were followed for a 90-day treatment period and 30 days of follow-up.

At baseline, the patient groups were well balanced for age (approximately 60 years), male gender (approximately 72%), medical history and comorbidities, and previous AF treatment.

Treatment Outcomes

A mean of 64.1% of patients receiving VKA spent time in the therapeutic range of an INR between 2.0 and 3.0. Operators had to use more unfractionated heparin with the edoxaban group than with the VKA group (evaluable subjects: n = 375, n = 178, respectively) to achieve an activated clotting time (ACT) above 300 s, and the edoxaban group had a shorter ACT (< .001 for both).

In the periprocedural and postprocedural period, a per protocol analysis showed the composite end point was achieved by 1.3% of the edoxaban group and 3.0% of the VKA group (hazard ratio, 0.42; 95% CI, 0.096 - 1.885; = .26). In a modified intention-to-treat analysis in which only patients who had actually undergone ablation were included, the rates were 2.7% and 1.7%, respectively, and also not statistically significant.

In terms of safety, "there were one ischemic and one hemorrhagic stroke, and both occurred in patients assigned to edoxaban. ISTH major bleeding events occurred at an incidence of 2.5% on edoxaban and 1.5% on VKA without any statistical significant difference between the two groups," Hohnloser reported. "Incidence of cardiac tamponade was low and similar in both treatment groups.

A limitation of the study is that it was exploratory and not powered to formally test superiority or noninferiority of edoxaban vs VKA. "Such a trial would have needed 3000 to 4000 patients and was thus deemed not to be affordable," Hohnloser said.

Prothrombotic State

Tatjana Potpara, MD, PhD, Belgrade University, Serbia, provided expert commentary after the ELIMINATE-AF study presentation. She said catheter ablation is associated with a prothrombotic state during the procedure and for some time afterward because of the manipulation within the heart and concomitant endothelial damage.

Periprocedural anticoagulation is associated with bleeding risk, including hemopericardium, cardiac tamponade, and vascular damage, so a careful balance between thromboembolism risk and bleeding risk must be achieved, she said.

She reviewed study outcomes for the four oral anticoagulants (OACs) now on the market. VENTURE-AF with rivaroxaban showed a low rate of major bleeding after catheter ablation and thus is a feasible treatment regimen. RE-CIRCUIT with dabigatran had fewer bleeding events compared with warfarin.

On a composite measure of all-cause death, stroke, and major bleeding, AXAFA-AF-NET showed that apixaban was safe and effective compared with warfarin and, finally, ELIMINATE-AF has shown edoxaban and a VKA each were associated with low rates of the primary end point.

"If you look at the outcome events across the four trials, the rates are exceptionally low," with an "assuringly low rate of major bleeding events and...low rates of composite outcomes," she said.

She noted that all of these trials involved sample sizes at least 10 times smaller than would be needed to make meaningful statistical comparisons between nonvitamin K oral anticoagulants (NOACs) and VKAs. Potpara warned that for anyone using an uninterrupted NOAC in patients undergoing AF ablation, "make sure that you know how to track what's used in the respective trial. Otherwise, you will be using probably off-label.

"However, should we change clinical practice in terms of switching patients from one OAC agent to another only for the purpose for ablation?" She answered her own question, saying there is no solid evidence to do so.

Hohnloser has served as a consultant, advisor, and/or speaker for Bayer Healthcare, BMS, Boehringer Ingelheim, Boston Scientific, Cardiome, Daiichi Sankyo, Gilead, Johnson & Johnson, Medtronic, Otsuka, Pfizer, Portola, Sanofi Aventis, Servier, and Zoll. Potpara had no disclosures.

European Heart Rhythm Association (EHRA) 2018. Presented March 18, 2019.


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