Renal function and outcomes in subclinical atrial fibrillation: a prespecified analysis of the ARTESIA trial

Background - Renal dysfunction commonly coexists with clinical atrial fibrillation and is associated with thromboembolism and bleeding. In a prespecified analysis of the Apixaban for the Reduction of Thrombo-Embolism in Patients with Device-Detected Subclinical Atrial Fibrillation (ARTESiA) trial, we investigated associations between renal function and prognosis in patients with subclinical atrial fibrillation (SCAF). Methods - In ARTESiA, participants with SCAF were randomised within a double-blind, double-dummy design to receive either guideline-indicated doses of apixaban or aspirin 81 mg daily. The primary efficacy endpoint was the composite of stroke or systemic embolism (SE); the primary safety endpoint was major bleeding. Multivariable Cox proportional hazards regression was conducted to explore the association of baseline creatinine clearance (CrCl) with outcomes and restricted cubic splines were fitted to capture non-linear associations. Treatment effect modification by renal function was assessed with interaction tests. Analyses were by intention-to-treat. Results - All 4012 trial participants had pre-randomisation creatinine measurements and were included. On average, those with lower CrCl were older, female, at lower body weight, had higher CHA2DS2-VASc scores and were more likely to meet apixaban dose reduction criteria. There were non-linear, inverse associations between declining renal function, and both major bleeding and death (Figure 1A). Below a CrCl of 60 mL/min, declining renal function was associated with higher risk of major bleeding (adjusted HR per 10 mL/min decrease 1.31, 95%CI 1.01–1.71; P=0.04), with no association above this threshold. Below a CrCl of 60 mL/min there was an increase in death from any cause (adjusted HR per 10 mL/min decrease 1.39, 95%CI 1.27–1.52, P<0.0001) and cardiovascular death (adjusted HR per 10 mL/min decrease 1.45, 95%CI 1.28–1.65, P<0.0001). Lower CrCl was not associated with increased risk of stroke or SE, nor did it modify treatment effects of apixaban versus aspirin with respect to reducing stroke/SE (Pinteraction=0.78) or increasing major bleeding (Pinteraction=0.73) (Figure 1B). Conclusion - In patients with SCAF, renal dysfunction is associated with increased major bleeding and death below a CrCl of 60 mL/min but does not influence stroke risk. Renal function did not modify the treatment effects of apixaban versus aspirin for any trial outcomes.Figure 1AFigure 1B