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

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.