Edoxaban Antithrombotic Therapy for Atrial Fibrillation and Stable Coronary Artery Disease

Authors, Journal, Affiliations, Type, DOI

• Min Soo Cho, Do-Yoon Kang, Jung-Min Ahn, Sung-Cheol Yun, et al. for the EPIC-CAD Investigators
• N Engl J Med 2024;391:2075-86 (published September 1, 2024; issue December 5, 2024)
• Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea (plus 17 additional South Korean sites)
• Multicenter, open-label, adjudicator-masked, randomized controlled trial (EPIC-CAD)
• Funded by CardioVascular Research Foundation, Daiichi Sankyo, Daewoong Pharmaceutical
• DOI: 10.1056/NEJMoa2407362

Overview

EPIC-CAD is the first adequately powered RCT directly testing edoxaban monotherapy versus dual antithrombotic therapy (edoxaban plus a single antiplatelet agent) in patients with atrial fibrillation and stable coronary artery disease. At 12 months, monotherapy was superior on the composite net adverse clinical events endpoint (6.8% vs 16.2%; HR 0.44; NNT 10.6), driven primarily by a two-thirds reduction in bleeding events. Major ischemic events were statistically similar between groups, though the trial was not powered to detect differences in ischemic outcomes. Key limitations include the open-label design, exclusive East Asian population, and the inherent limitation of a net clinical outcome primary endpoint that favours the less potent antithrombotic strategy.

Keywords

Atrial fibrillation, stable coronary artery disease, edoxaban, dual antithrombotic therapy, antiplatelet, anticoagulation, net adverse clinical events, CHA2DS2-VASc, HAS-BLED, EPIC-CAD

Key Takeaways

Background and Rationale

• Patients with AF need OAC for stroke prevention; patients with stable CAD need antiplatelet therapy to prevent ischemic events. Combined use increases bleeding risk significantly.
• Prior RCTs (OAC-ALONE with warfarin; AFIRE with rivaroxaban) evaluated this question but were terminated prematurely or used a non-standard rivaroxaban dose (15 mg or 10 mg in AFIRE). EPIC-CAD was designed to use standard-dose edoxaban and include both revascularized and medically managed stable CAD.

Trial Design

• 1:1 randomization to edoxaban monotherapy (standard dose) vs edoxaban + single antiplatelet (aspirin or P2Y12 inhibitor per physician discretion)
• Edoxaban dose: 60 mg once daily (57.5%) or 30 mg once daily (42.5%; dose-reduced for CrCl 15–50 mL/min, weight ≤60 kg, or P-glycoprotein inhibitor use)
• In the dual therapy arm: aspirin (61.8%) or clopidogrel (37.8%) used as the antiplatelet
• 18 sites in South Korea; May 2019–September 2022; 12-month follow-up

Population

• 1,040 patients; mean age 72.1±8.2 years; 22.9% women
• AF: 55.3% paroxysmal; 44.7% persistent/permanent
• Stable CAD: 65.7% prior revascularization (PCI ≥6 months or ACS-PCI ≥12 months ago); 34.3% medically managed (≥50% epicardial stenosis on angiography or CTA)
• Mean CHA₂DS₂-VASc: 4.3±1.5; Mean HAS-BLED: 2.2±0.8 (all patients high thromboembolic risk by design)

Primary Outcome — Net Adverse Clinical Events (NACE)

• NACE = composite of death, MI, stroke, systemic embolism, unplanned urgent revascularization, or major/CRNM bleeding (ISTH definition) at 12 months
• Edoxaban monotherapy: 6.8% vs dual therapy: 16.2%; HR 0.44 (95% CI 0.30–0.65; P<0.001)
• NNT = 10.6 (95% CI 6.1–15.2) to avoid one primary-outcome event at 12 months

Secondary Outcomes — Ischemic

• Major ischemic events (death + MI + ischemic stroke + SE): 1.6% vs 1.8%; HR 1.23 (95% CI 0.48–3.10); NS
• Any ischemic events (adding unplanned urgent revascularization): similar in both groups
• Stent thrombosis (in stented patients only): rates were low and not numerically reported as significantly different

Secondary Outcomes — Bleeding

• Major + CRNM bleeding (ISTH): 4.7% vs 14.2%; HR 0.34 (95% CI 0.22–0.53)
• Major bleeding (ISTH): 1.3% vs 4.5%; HR 0.32 (95% CI 0.14–0.73)

Sensitivity and Subgroup Analyses

• Per-protocol analysis consistent with ITT
• Primary outcome benefit of monotherapy was consistent across all prespecified subgroups (including prior PCI vs medically managed, aspirin vs P2Y12 as the antiplatelet agent, and edoxaban dose)
• Treatment effect on bleeding was also consistent across subgroups

Context: Relation to Prior Trials

• OAC-ALONE (2019, warfarin): OAC alone vs OAC + antiplatelet in AF + stable CCD >1 year post-PCI; noninferiority not demonstrated; terminated early; inconclusive
• AFIRE (2019, rivaroxaban): rivaroxaban monotherapy noninferior to rivaroxaban + antiplatelet for ischemic outcomes; superior for bleeding; however, predominantly low-risk patients and non-standard rivaroxaban dose (15 mg or 10 mg); EPIC-CAD uses standard edoxaban and includes medically managed CAD
• EPIC-CAD is the largest and most definitive trial to date in this population

Limitations of the Document

• Open-label design: risk of reporting/ascertainment bias (mitigated by independent, blinded adjudication committee)
• Underpowered for ischemic events: trial was not designed to detect meaningful differences in death, MI, or stroke individually
• Net clinical outcome primary endpoint: inherently biases toward less potent antithrombotic due to higher absolute bleeding than ischemic event rate
• Dynamic risk changes (HAS-BLED, CHA₂DS₂-VASc over time) not captured
• Exclusive East Asian population: different propensity for ischemic/bleeding complications vs Western populations; limits generalizability
• Women underrepresented (22.9%)
• All-Korean single-country enrollment may not reflect global practice

Key Concepts Mentioned

• concepts/AF-Stable-CAD-Antithrombotic — central topic of this trial
• concepts/DAPT-Strategies — replaced by OAC monotherapy in stable phase; AFIRE/EPIC-CAD context
• concepts/CHA2DS2-VA — used for enrollment (CHA₂DS₂-VASc ≥2) and risk stratification

Key Entities Mentioned

• entities/Atrial-Fibrillation — indication for anticoagulation in this trial
• entities/Chronic-Coronary-Disease — stable CAD population studied

Wiki Pages Updated

• Created: wiki/sources/edoxaban-af-cad-nejm-2024.md (this file)
• Created: wiki/concepts/AF-Stable-CAD-Antithrombotic.md
• Updated: wiki/entities/Atrial-Fibrillation.md — added stable CAD section
• Updated: wiki/entities/Chronic-Coronary-Disease.md — added EPIC-CAD reference
• Updated: wiki/concepts/DAPT-Strategies.md — added EPIC-CAD reference
• Updated: wiki/sourceindex.md
• Updated: wiki/wikiindex.md