Renal Dysfunction as a Predictor of Stroke and Systemic Embolism in Patients With Nonvalvular Atrial Fibrillation Validation of the R2CHADS2 Index in the ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation) Study Cohorts

Background-We sought to define the factors associated with the occurrence of stroke and systemic embolism in a large, international atrial fibrillation (AF) trial. Methods and Results-In ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation), 14 264 patients with nonvalvular AF and creatinine clearance >= 30 mL/min were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards modeling was used to identify factors at randomization independently associated with the occurrence of stroke or non-central nervous system embolism based on intention-to-treat analysis. A risk score was developed in ROCKET AF and validated in ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation), an independent AF patient cohort. Over a median follow-up of 1.94 years, 575 patients (4.0%) experienced primary end-point events. Reduced creatinine clearance was a strong, independent predictor of stroke and systemic embolism, second only to prior stroke or transient ischemic attack. Additional factors associated with stroke and systemic embolism included elevated diastolic blood pressure and heart rate, as well as vascular disease of the heart and limbs (C-index 0.635). A model that included creatinine clearance (R(2)CHADS(2)) improved net reclassification index by 6.2% compared with CHA(2)DS(2) VASc (C statistic=0.578) and by 8.2% compared with CHADS(2) (C statistic=0.575). The inclusion of creatinine clearance < 60 mL/min and prior stroke or transient ischemic attack in a model with no other covariates led to a C statistic of 0.590. Validation of R(2)CHADS(2) in an external, separate population improved net reclassification index by 17.4% (95% confidence interval, 12.1%-22.5%) relative to CHADS(2). Conclusions-In patients with nonvalvular AF at moderate to high risk of stroke, impaired renal function is a potent predictor of stroke and systemic embolism. Stroke risk stratification in patients with AF should include renal function. Clinical Trial Registration-URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00403767. (Circulation. 2013;127:224-232.)