University of Chronic kidney disease, time in therapeutic range and adverse clinical outcomes in anticoagulated patients with non-valvular atrial fibrillation: observations from the SPORTIF trials

Background: Chronic kidney disease (CKD) is highly prevalent in atrial fibrillation (AF) patients and associated with an increased risk of adverse outcomes. Our objectives were to study clinical features associated with CKD in AF patients and the impact of CKD on anticoagulation control, as reflected by time in therapeutic range (TTR). We also determined the impact of CKD and TTR in predicting adverse outcomes. Methods and Results: We analysed pooled datasets from SPORTIF III and V trials, including 3,646 patients assigned to warfarin with data on renal function. CKD (creatinine clearance <60 ml/min) was present in 952 (26%) patients. TTR was higher in patients with normal renal function compared to those with CKD (p<0.001). On logistic analysis, chronic AF and male sex were associated with TTR>70%, whilst diabetes mellitus, aspirin use and CKD were inversely associated with TTR>70%. On Cox regression analysis, CKD was an independent predictor for stroke (p=0.006) and death (p<0.001). TTR>70% was independently associated with a lower risk of stroke (p=0.024), death (p=0.001) and major bleeding (p=0.001). Conclusions: CKD is highly prevalent among AF patients and a risk factor for stroke and death. Adjusting for CKD, good quality anticoagulation control (TTR>70%) was an independent predictor for lower risks of stroke, death and major bleeding. Survival analysis, assessed by an intention-to-treat approach, was performed according to the presence of CKD and differences in survival distributors between subgroups were analysed using the Log-Rank test. Evaluation of the clinical characteristics significantly associated with outcomes was performed using a Cox proportional hazards analysis, corrected according to thromboembolic risk, performed with CKD both as a categorical variable and CrCl as a continuous variable. All demographic variables, comorbidities and risk factors analysed at baseline underwent a univariate analysis. All variables with a p-value <0.10 for the association with clinical outcome at the univariate analysis, were inserted into the forward stepwise multivariate model. A backward model was then performed to verify the results of the forward one. A two-sided p value <0.05 was considered statistically significant. All analyses were performed using SPSS v. 22.0 (IBM, NY, USA) and R v. 3.2. 1 (The R Foundation). Our results demonstrate that even in AF patients treated with warfarin, CKD was still associated with a higher incidence of stroke, independent of other concomitant risk factors. These data support previous findings from another prospective randomised trial, where the presence of a CrCl <60 ml/min was associated with two-fold higher risk of stroke compared with those with CrCl ≥ 60 ml/min(Apostolakis et al., 2013). Importantly, we show that the predictive ability of CKD in identifying patients with a greater risk of stroke was independent of anticoagulation control, as reflected by the TTR, notwithstanding the latter being a strong predictor of adverse in 2007).