Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial

doi:10.1016/S0140-6736(19)31872-0

The Lancet

Volume 394, Issue 10206, 12–18 October 2019, Pages 1335-1343

https://doi.org/10.1016/S0140-6736(19)31872-0 Get rights and content

Summary

Background

We aimed to assess the safety of edoxaban in combination with P2Y12 inhibition in patients with atrial fibrillation who had percutaneous coronary intervention (PCI).

Methods

ENTRUST-AF PCI was a randomised, multicentre, open-label, non-inferiority phase 3b trial with masked outcome evaluation, done at 186 sites in 18 countries. Patients had atrial fibrillation requiring oral anticoagulation, were aged at least 18 years, and had a successful PCI for stable coronary artery disease or acute coronary syndrome. Participants were randomly assigned (1:1) from 4 h to 5 days after PCI using concealed, stratified, and blocked web-based central randomisation to either edoxaban (60 mg once daily) plus a P2Y12 inhibitor for 12 months or a vitamin K antagonist (VKA) in combination with a P2Y12 inhibitor and aspirin (100 mg once daily, for 1–12 months). The edoxaban dose was reduced to 30 mg per day if one or more factors (creatinine clearance 15–50 mL/min, bodyweight ≤60 kg, or concomitant use of specified potent P-glycoprotein inhibitors) were present. The primary endpoint was a composite of major or clinically relevant non-major (CRNM) bleeding within 12 months. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of their assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02866175, is closed to new participants, and follow-up is completed.

Findings

From Feb 24, 2017, through May 7, 2018, 1506 patients were enrolled and randomly assigned to the edoxaban regimen (n=751) or VKA regimen (n=755). Median time from PCI to randomisation was 45·1 h (IQR 22·2–76·2). Major or CRNM bleeding events occurred in 128 (17%) of 751 patients (annualised event rate 20·7%) with the edoxaban regimen and 152 (20%) of 755 patients (annualised event rate 25·6%) patients with the VKA regimen; hazard ratio 0·83 (95% CI 0·65–1·05; p=0·0010 for non-inferiority, margin hazard ratio 1·20; p=0·1154 for superiority).

Interpretation

In patients with atrial fibrillation who had PCI, the edoxaban-based regimen was non-inferior for bleeding compared with the VKA-based regimen, without significant differences in ischaemic events.

Funding

Daiichi Sankyo.

Introduction

Non-vitamin K antagonist oral anticoagulants (NOAC) are rapidly replacing vitamin K antagonists (VKAs) as the treatment of choice for stroke prevention in patients with non-valvular atrial fibrillation who are at increased thromboembolic risk (ie, CHA₂DS₂-VASc score ≥2).1, 2 About 15% of patients with atrial fibrillation might require percutaneous coronary interventions (PCIs) with stent placement to treat obstructive coronary artery disease.³ The coexistence of atrial fibrillation with acute coronary syndrome or stable coronary artery disease raises concern about co-treatment with different antithrombotic drugs in the case of PCI. Dual antiplatelet therapy (DAPT) with acetylsalicylic acid (aspirin) and P2Y12 antagonist is recommended after PCI and patients requiring DAPT often also require treatment with oral anticoagulation, including patients with atrial fibrillation.4, 5 DAPT in combination with oral anticoagulation (triple therapy) is associated with high risk of bleeding.6, 7 Three randomised trials evaluated standard or reduced doses of NOACs in patients with atrial fibrillation who had undergone PCI and cumulatively added strength to the concept that abandoning aspirin might improve safety towards bleeding in these patients.8, 9, 10

Edoxaban is as effective as a VKA with respect to the prevention of stroke or systemic embolism and is associated with significantly lower incidence of bleeding and death from cardiovascular causes.¹¹ From the patient perspective, edoxaban therapy has been shown to be more convenient to use than VKA.12, 13 However, the effects of edoxaban in combination with a P2Y12 inhibitor in the setting of PCI are unexplored.¹⁴

Research in context

Evidence before this study

We did a systematic search on PubMed for studies published up to July 13, 2019, with no language restrictions. The following keywords were used in different combinations: “percutaneous coronary intervention”, “PCI”, “coronary stenting”, “acute coronary syndrome”, “ACS”, “atrial fibrillation”, “AF”, “apixaban”, “rivaroxaban”, “edoxaban”, “dabigatran”, “vitamin K antagonist”, “warfarin”, “phenprocoumon”, “oral anticoagulation”, “oral anticoagulants”, “dual antithrombotic therapy”, “dual therapy”, “triple therapy”, “triple antithrombotic therapy”, “dual antiplatelet therapy”, “clopidogrel”, “aspirin”, and “randomised trial”. References of previous systematic reviews and meta-analyses were also screened for relevant studies. For this meta-analysis, we included all randomised controlled trials in patients with atrial fibrillation who received percutaneous coronary intervention (PCI) in at least 50% of the sample and were allocated to dual antithrombotic therapy (DAT) consisting of any non-vitamin K antagonist oral anticoagulant (NOAC) in combination with a P2Y12 inhibitor or triple antithrombotic therapy (TAT) consisting of any vitamin K antagonist (VKA) in combination with dual antiplatelet therapy (DAPT). Three completed trials (PIONEER-AF PCI, RE-DUAL PCI, and AUGUSTUS) were identified. The PIONEER-AF PCI (N=2124) trial showed either low-dose rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor for 12 months or very-low-dose rivaroxaban (2·5 mg twice daily) plus DAPT for 1, 6, or 12 months was associated with lower rate of clinically significant bleeding (a composite of major bleeding or minor bleeding according to TIMI criteria or bleeding requiring medical attention) compared with standard therapy with a VKA plus DAPT for 1, 6, or 12 months. In the RE-DUAL PCI (N=2725) trial the ISTH classification bleeding risk was lower among those who received dual therapy with dabigatran (110 or 150 mg twice daily) and a P2Y12 inhibitor than those who received TAT. The AUGUSTUS (N=4614) trial assessed the safety and efficacy of standard-dose apixaban (5 mg twice daily) compared with a VKA and of low-dose acetylsalicylic acid (aspirin) compared with placebo, on a background of concomitant P2Y12 inhibitor therapy for 6 months in patients with atrial fibrillation and recent acute coronary syndrome or PCI. DAT use was associated with a greater than 40% reduction of ISTH-defined major or clinically relevant non-major (CRNM) bleeding compared with TAT.

Added value of this study

This is the first trial testing an edoxaban-based DAT versus a VKA-based TAT in patients with atrial fibrillation who had PCI. This study showed that DAT consisting of edoxaban in combination with an oral P2Y12 inhibitor is non-inferior to TAT (VKA, oral P2Y12 inhibitor, and 1-month to 12-month aspirin) with respect to the occurrence of major or CRNM bleeding at 12 months. The composite of cardiovascular death, stroke, myocardial infarction, definite stent thrombosis, or systemic embolic events, as well as its individual components, did not differ between groups.

Implications of all the available evidence

We pooled the four trials using crude number of events retrieved from each study and a random-effects model (Mantel-Haenszel method). Given the objective of this meta-analysis, we only selected treatment groups with NOAC-based DAT or VKA-based TAT from the included trials. Treatment effect was reported as risk ratio and 95% CI. A DAT consisting of a NOAC and an oral P2Y12 inhibitor compared with TAT based on VKA and DAPT was associated with lower risks of major or CRNM bleeding events and similar risks of major adverse cardiovascular events, all-cause death, stroke, stent thrombosis, or myocardial infarction. Thus, NOAC-based DAT was safer and as effective as VKA-based TAT (appendix p 41).

We conducted a trial for the evaluation of the safety and efficacy of an edoxaban-based antithrombotic regimen in patients with atrial fibrillation following successful percutaneous coronary intervention (the ENTRUST-AF PCI trial) to assess the safety and efficacy of an edoxaban-based versus a VKA-based antithrombotic regimen among patients with atrial fibrillation who had undergone PCI.¹⁴

Section snippets

Study design and participants

The ENTRUST-AF PCI trial was a randomised, multicentre, open-label, phase 3b study with masked outcome assessments by an independent clinical event committee done at 186 sites in 18 countries (appendix pp 8–14).¹⁴ Eligible patients had atrial fibrillation requiring oral anticoagulation, were aged at least 18 years, and had a successful PCI for stable coronary artery disease or acute coronary syndrome.¹⁴ Patients with non-valvular atrial fibrillation not secondary to a reversible disorder were

Results

From Feb 24, 2017, to May 7, 2018, 1506 PCI patients with atrial fibrillation were randomly assigned to receive an open-label edoxaban-based regimen (n=751) or a VKA-based regimen (n=755); 746 (99%) patients assigned to the edoxaban-based regimen and 740 (98%) assigned to the VKA regimen received at least one dose of their assigned drug (figure 1).

The characteristics of the patients at baseline were well balanced between the groups (table 1). The indication for the index PCI was acute coronary

Discussion

The ENTRUST-AF PCI trial showed that, among patients with atrial fibrillation who had successful PCI, a full-dose anticoagulation therapy with edoxaban 60 mg once daily plus a P2Y12 inhibitor is non-inferior to a triple therapy with VKA (aspirin given for 1–12 months) regarding the risks of major or CRNM bleeding events at 12 months. This difference for the primary bleeding outcome was mainly attributable to the CRNM bleeding events. The edoxaban dual therapy regimen and the triple VKA regimen

Data sharing

The ENTRUST-AF PCI trial is sponsored by Daiichi Sankyo. Multiple substudies are predefined. Internal investigators, who actively participated in the study, and who provide a methodologically sound study proposal will be granted priority access to the study data for 60 months. After 60 months, access is extended to external investigators not affiliated to the trial. Study proposals can be filed at the Vivli website.

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ArticlesEdoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Data sharing

Lancet

J Am Coll Cardiol

Int J Cardiol

Lancet

Am Heart J

J Thromb Haemost

Lancet

J Am Coll Cardiol

J Am Coll Cardiol

Lancet

Lancet

2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS

Eur Heart J

2018 ESC/EACTS guidelines on myocardial revascularization

Eur Heart J

Articles
Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial