Cardiology · Medical Literature
Impact of renal function on edoxaban antithrombotic therapy in patients with atrial fibrillation and stable coronary artery disease: a prespecified analysis of the EPIC-CAD trial.
Abstract
Renal function is a critical factor of ischaemic and bleeding risks in patients with atrial fibrillation (AF) receiving antithrombotic therapy. This study aimed to evaluate the impact of renal dysfunction in patients with AF and stable coronary artery disease (CAD) undergoing antithrombotic therapy. The Edoxaban Versus Edoxaban With antiPlatelet Agent In Patients With Atrial Fibrillation and Chronic Stable Coronary Artery Disease (EPIC-CAD) trial randomised patients to edoxaban monotherapy or dual antithrombotic therapy (edoxaban plus a single antiplatelet agent). In this prespecified analysis, patients were stratified by creatinine clearance into low (<50 mL/min) or high (≥50 mL/min) groups according to edoxaban dose-reduction criteria. The primary endpoint was net adverse clinical events (NACE: death from any cause, myocardial infarction, stroke, systemic embolism, urgent revascularisation, or major/clinically relevant non-major bleeding) at 12 months. Of 1,040 randomised patients, 252 (24.2%) had low creatinine clearance; these patients were older and had more comorbidities compared with the 788 patients (75.8%) with high creatinine clearance. Patients with low creatinine clearance experienced higher risks of NACE (hazard ratio [HR] 1.72, 95% confidence interval [CI]: 1.19-2.49; p=0.004), ischaemic events (HR 2.70, 95% CI: 1.09-6.70; p=0.032), and bleeding (HR 1.54, 95% CI: 1.01-2.34; p=0.046). At 12 months, edoxaban monotherapy reduced NACE compared with dual therapy in both the low (12.1% vs 21.7%, HR 0.52, 95% CI: 0.28-0.98; p=0.042) and high creatinine clearance groups (5.2% vs 14.5%, HR 0.40, 95% CI: 0.25-0.65; p<0.001), with no interaction (p for interaction=0.53). In patients with AF and stable CAD, edoxaban monotherapy led to a lower risk of primary NACE than dual antithrombotic therapy, regardless of renal function. (ClinicalTrials.gov: NCT03718559).
Clinical relevance
In patients with atrial fibrillation (AF) and stable coronary artery disease (CAD), does the benefit of edoxaban monotherapy over dual antithrombotic therapy (edoxaban plus a single antiplatelet agent) on net adverse clinical events differ according to renal function, stratified by creatinine clearance <50 vs. ≥50 mL/min? __SNAPSHOT__ {"studyDesign":"Prespecified subgroup analysis of a multicenter, open-label, randomized controlled trial (EPIC-CAD; NCT03718559)","setting":"18 sites in South Korea (single-country, East Asian academic/tertiary center setting)","sampleSize":"n=1,040 total (low CrCl [<50 mL/min]: n=252 [24.2%]; high CrCl [≥50 mL/min]: n=788 [75.8%]); parent trial: edoxaban monotherapy n=524, dual antithrombotic therapy n=516","population":"Adults with high-risk AF (CHA2DS2-VASc ≥2) and stable CAD, defined as coronary revascularization ≥6 months prior (chronic coronary syndrome), ≥12 months prior (post-ACS), or anatomically confirmed medically managed CAD; mean age 72.1 years, ~23% women, mean CHA2DS2-VASc 4.3, mean HAS-BLED 2.2, prior revascularization in 65.7%; low CrCl subgroup was older with more comorbidities","intervention":"Edoxaban monotherapy: 60 mg once daily (dose-reduced to 30 mg daily if CrCl <50 mL/min, low body weight, or concomitant P-gp inhibitor use)","comparator":"Dual antithrombotic therapy: edoxaban (same dose-reduction rules) plus a single antiplatelet agent (aspirin or a P2Y12 inhibitor)","primaryOutcome":"Net adverse clinical events (NACE) at 12 months: composite of death from any cause, myocardial infarction, stroke, systemic embolism, urgent revascularization, or major/clinically relevant non-major bleeding (CRNMB)","followUp":"12 months","fundingSource":"Mixed: CardioVascular Research Foundation (South Korea; non-profit), Daiichi Sankyo (industry; edoxaban manufacturer), and Daewoong Pharma (industry)"}
Key findings
Across the full EPIC-CAD trial (parent), edoxaban monotherapy was associated with a substantially lower NACE rate versus dual antithrombotic therapy (6.8% vs. 16.2%; HR 0.44, 95% CI 0.30–0.65; p<0.001), with the benefit driven primarily by a reduction in bleeding (major or CRNMB: 4.7% vs. 14.2%). In this prespecified renal function analysis, patients with low CrCl (<50 mL/min; n=252) had significantly higher baseline risks: NACE HR 1.72 (95% CI 1.19–2.49; p=0.004), ischemic events HR 2.70 (95% CI 1.09–6.70; p=0.032), and bleeding HR 1.54 (95% CI 1.01–2.34; p=0.046) compared with the high CrCl group. Despite this elevated risk, edoxaban monotherapy reduced NACE in both renal strata: low CrCl group: 12.1% vs. 21.7% (HR 0.52, 95% CI 0.28–0.98; p=0.042); high CrCl group: 5.2% vs. 14.5% (HR 0.40, 95% CI 0.25–0.65; p<0.001). The interaction p-value for treatment effect by renal group was 0.53, indicating no statistically significant treatment heterogeneity by renal function. NNT at 12 months (calculated): low CrCl group ≈10.4; high CrCl group ≈10.7. Absolute risk reduction was numerically larger in the low CrCl subgroup (9.6 percentage points) versus the high CrCl subgroup (9.3 percentage points), though the interaction test was non-significant. Specific adverse event breakdown by renal stratum (e.g., ischemic events and bleeding events separately within each treatment arm by CrCl group) was not reported in the available abstract.
Practice implications
This prespecified analysis establishes that the benefit of edoxaban monotherapy over dual antithrombotic therapy on net clinical outcomes is consistent regardless of renal function category (CrCl <50 vs. ≥50 mL/min) in patients with AF and stable CAD. The study confirms, as a secondary finding, that renally impaired patients carry substantially higher absolute risks of both ischemic and bleeding events—making the choice of antithrombotic regimen especially consequential in this population. The consistent treatment effect across renal strata (non-significant interaction p=0.53) supports the generalizability of the monotherapy strategy to patients meeting edoxaban dose-reduction criteria. However, several limitations affect the strength of inference: (1) Only an abstract is publicly available for this prespecified analysis; full event-level data (e.g., individual NACE components by renal stratum and treatment arm, bleeding severity breakdown) are not reported and were not reviewed. (2) The analysis was stratified by a binary CrCl threshold (the edoxaban dose-reduction cut-point), not by continuous renal function, so the impact of more severe renal impairment (e.g., CrCl <30 mL/min) or end-stage kidney disease cannot be assessed. Patients with very severe CKD or on dialysis were likely excluded. (3) The 95% CIs in the low CrCl subgroup are notably wide (HR 0.52, 95% CI 0.28–0.98), including a point estimate close to 1.0, reflecting limited statistical power in this smaller subgroup (n=252). The p-value of 0.042 is nominally significant but borderline. (4) The trial was conducted entirely in South Korea; findings may not be fully generalizable to non-East Asian populations who may have different pharmacokinetic profiles, dietary patterns, or background risk. (5) The open-label design introduces potential ascertainment bias, particularly for soft bleeding endpoints. (6) Industry co-sponsorship by Daiichi Sankyo (edoxaban manufacturer) should be noted when appraising results. __LIMITATIONS__ Subgroup analysis: the low CrCl group (n=252) was underpowered relative to the full trial, yielding wide confidence intervals (HR 0.52, 95% CI 0.28–0.98) that approach statistical non-significance.,Binary renal stratification by edoxaban dose-reduction threshold (CrCl <50 vs. ≥50 mL/min) precludes assessment of a gradient effect across the full spectrum of renal function; patients with CrCl <15–20 mL/min or on dialysis were almost certainly underrepresented or excluded.,Open-label design (no blinding of participants, clinicians, or outcome assessors) introduces risk of performance and detection bias, particularly for subjective or soft bleeding outcomes.,Single-country trial (South Korea only); results may not generalize to non-Asian populations or healthcare systems with different antiplatelet preferences, dietary vitamin K intake, or baseline risk profiles.,Mixed industry and non-profit funding (Daiichi Sankyo co-sponsored; edoxaban is a Daiichi Sankyo product), which represents a potential conflict of interest.,12-month follow-up only; long-term comparative safety and efficacy data beyond one year are not available from this study.,Composite NACE endpoint combines ischemic and bleeding outcomes of disparate clinical severity; net clinical benefit framing may obscure differential effects on hard ischemic endpoints (stroke, MI) versus bleeding.,Full component-level event data by renal stratum and treatment arm are not available in the abstract, limiting granular interpretation.,Only abstract-level data were available for this specific prespecified analysis at the time of this summary. __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ In patients with AF and stable CAD, edoxaban monotherapy was associated with fewer net adverse clinical events than dual antithrombotic therapy (edoxaban plus antiplatelet) across both low and high creatinine clearance strata, with a non-significant interaction by renal function (p=0.53). Renally impaired patients (CrCl <50 mL/min) had markedly higher absolute ischemic and bleeding risks, making the net clinical benefit of monotherapy numerically comparable in absolute terms to those with preserved renal function. These findings support applying the EPIC-CAD monotherapy strategy to renally impaired patients meeting standard edoxaban dose-reduction criteria, though confirmatory data in more severe CKD and non-Asian populations remain needed.