What does this research mean for the field?

Patients with CKD Stage 3 and 4 on edoxaban had significantly increased risks for cardiovascular death (Stage 3: HR 2.11; Stage 4: HR 6.97) compared to CKD Stage 1. Novelty: ClaimNovelty.CONFIRMATORY. Consensus alignment: ConsensusAlignment.SUPPORTS_CONSENSUS.

February 6, 2026

Renal function and long-term outcomes in edoxaban-treated patients: A subanalysis from ETNA-AF Europe 4 years follow up

Key Result

Edoxaban doses were safe and effective for AF patients with CKD Stages 1-3, with no increased stroke risk; Stage 3-4 patients had higher CV death risk (HR 2.11-6.97).

Key Points

This research investigates how renal function affects the safety and effectiveness of edoxaban in patients with atrial fibrillation, particularly across different stages of chronic kidney disease.
Long-term data from ETNA-AF-Europe 4YFU involving 9,114 patients prescribed edoxaban.
Patients stratified by chronic kidney disease stages based on estimated glomerular filtration rate (eGFR).
Cox regression analyzed risks of stroke and bleeding comparing advanced CKD stages against stage 1, adjusting for potential confounders.
Advanced CKD stages (3 and 4) showed increased risks for stroke and cardiovascular death compared to CKD Stage 1.
Significantly higher risk of bleeding in CKD stages 2-4 was noted, particularly for major bleeding events.
Statistically significant cardiovascular death risks were found in CKD stages 3 and 4, highlighting the need for careful risk assessment.

Structured PICO

Does renal function impact the safety and effectiveness of recommended edoxaban dosages in patients with atrial fibrillation?

Population

9,114 patients with atrial fibrillation (AF) prescribed recommended edoxaban doses (30 mg or 60 mg), stratified by CKD stages (Stage 1: n=2,064; Stage 2: n=4,885; Stage 3: n=1,985; Stage 4: n=135).

Intervention

Edoxaban 30 mg or 60 mg in patients with CKD Stages 2-4

Comparator

Edoxaban 30 mg or 60 mg in patients with CKD Stage 1 (eGFR ≥90 mL/min/1.73m2)

Outcome

Stroke and cardiovascular (CV) deathhard clinical

Recommended edoxaban doses are effective and safe for stroke prevention in AF patients with mild to moderate CKD, though advanced CKD remains a strong predictor of CV death.

Main Result

Absolute Event Rate: 0% vs 0%

Abstract

Abstract Background The four-year follow-up (4YFU) data from ETNA-AF-Europe (NCT02944019) highlighted the long-term safety and effectiveness of edoxaban in patients with atrial fibrillation (AF), with relatively low rates of death, stroke, major bleeding, and intracranial haemorrhage. Purpose This subanalysis of the ETNA-AF-Europe 4YFU evaluates the impact of renal function on the safety and effectiveness of recommended edoxaban dosages, stratified by chronic kidney disease (CKD) stages (estimated glomerular filtration rate eGFR CKD-EPI). Methods Of the 13,164 patients enrolled in the ETNA-AF-Europe 4YFU, 9,114 patients who were prescribed edoxaban doses (30 mg or 60 mg) as recommended in the summary of product characteristics (SmPC) were stratified by CKD stages: Stage 1 (eGFR ≥90 mL/min/1.73m2; n=2,064), Stage 2 (eGFR 60≤90 mL/min/1.73m2; n=4,885), Stage 3 (eGFR 30≤60 mL/min/1.73m2; n=1,985), Stage 4 (eGFR 15≤30 mL/min/1.73m2; n=135). Both non-adjusted and adjusted Hazard Ratios (HR) and 95% confidence intervals (CI) were calculated by Cox regression comparing CKD Stages 2-4 against CKD Stage 1. Adjustments were made for age, sex, body weight, and clinical risk scores (modified CHA2DS2-VASc and HAS-BLED). Results More advanced stages of CKD were associated with older age, lower body weight, more frequent dose reductions, increased frailty, and a higher prevalence of cardiovascular (CV) and bleeding-related risk factors (Table). Compared to CKD Stage 1, patients with Stages 3 and 4 had increased risks for stroke (Stage 3: HR 95% CI 1.90 1.24–2.88, p=0.003; Stage 4: p=0.824, non-significant) and CV death (Stage 3: HR 95% CI 4.67 3.13–6.97 and Stage 4: HR 95% CI 14.45 8.27–25.25, both p0.001). More advanced stages of CKD were also associated with significantly increased risk for safety outcomes such as any bleeding (Stages 2-3, p0.001; stage 4, p=0.013), major bleeding (all p≤0.001), and major gastrointestinal bleeding (Stage 2, p=0.027; stages 3-4, p0.001) (Figure, left panel). After adjusting for age, sex, body weight, and clinical risk scores, the analysis indicates that the risk of stroke and any bleeding in patients with CKD Stages 2, 3, and 4 does not show a statistically significant difference compared to those with CKD Stage 1 (Figure, right panel). However, there were increased risks of cardiovascular (CV) death for CKD Stage 3 and 4 patients (Stage 3: HR 95% CI: 2.11 1.32–3.39, p=0.002 and Stage 4: HR 95% CI: 6.97 3.75, 12.95, p0.001) and of major bleedings for CKD Stage 3 patients (HR95% CI: 1.72 1.08; 2.74, p=0.023). Conclusions These findings reaffirm the effectiveness and safety of recommended edoxaban doses in AF patients with mild to moderate kidney disease stages (Stages 1-3), particularly in reducing stroke incidence and bleeding events. In patients with advanced CKD (Stage 4), consideration of competing causes of cardiovascular death emerges as an important component for therapeutic decisions.

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