Treatment Consistency Across Levels of Baseline Renal Function With Rivaroxaban or Warfarin
Authors: Samuel M. Lindner, Christopher B. Fordyce, Anne S. Hellkamp, Yuliya Lokhnygina, Jonathan P. Piccini, Günter Breithardt, Kenneth W. Mahaffey, Daniel E. Singer, Werner Hacke, Jonathan L. Halperin, Graeme J. Hankey, Scott D. Berkowitz, Christopher C. Nessel, Richard C. Becker, Keith A.A. Fox, Manesh R. Patel
Journal: Circulation (2017)

Patients with impaired renal function have higher rates of bleeding and thromboembolism. 1 Our group recently described the impact of worsening renal function on patients in the ROCKET AF study (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) (ClinicalTrials.gov.Unique identifier: NCT00403767). 2In the process of publishing these findings, questions arose from reviewers regarding the influence of baseline creatinine clearance (CrCl) on trial outcomes in ROCKET AF. 3 Bohula et al 4 demonstrated higher relative rates of thromboembolism in those with CrCl >95 mL/min treated with edoxaban in the ENGAGE TIMI-AF 48 trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation -Thrombolysis in Myocardial Infarction 48).We present the findings of an analysis using data from ROCKET AF 3 to evaluate the consistency of treatment effect of rivaroxaban versus warfarin across the full range of baseline CrCl included in the trial.ROCKET AF included 14 264 patients with nonvalvular atrial fibrillation (AF).Patients were randomly assigned to 20 mg rivaroxaban once daily (15 mg once daily in patients with a CrCl of 30-49 mL/min) or dose-adjusted warfarin (target international normalized ratio 2.5, range 2.0-3.0).Further description of the ROCKET AF results and design has been published previously. 3,5All patients provided written informed consent, and approval by appropriate ethics committees was obtained at all sites.We included 14 221 patients with CrCl data who received the study drug.We examined the primary efficacy end point of stroke or systemic embolism (SE); the principal safety end point of major or nonmajor clinically relevant bleeding; the secondary efficacy outcomes of ischemic stroke, hemorrhagic stroke, and SE; and the secondary safety outcomes of major bleeding, intracranial hemorrhage, and nonmajor clinically relevant bleeding.Event rates were generated for subgroups defined by randomized treatment and baseline renal function assessed by Cockroft-Gault formula: moderate renal impairment (CrCl 30 to <50 mL/min, n=2950), mild renal impairment (CrCl 50 to <80 mL/min, n=6565), and normal renal function (CrCl ≥80 mL/min, n=4706).An additional subgroup analyzing primary efficacy and principal safety outcomes in those with CrCl >95 mL/min (n=2486) was chosen to investigate effectiveness in those with high CrCl based on the findings of Bohula et al. 4 The relationship of treatment to outcomes within CrCl levels was assessed 2 ways: once with CrCl subgroups and once with CrCl as a continuous variable, using Cox proportional hazards models adjusted for previously identified predictors of outcomes.The rates of the primary efficacy end point of stroke and SE increased with declining CrCl (1.23 events per 100 patient-years for CrCl ≥80, 1.84 for CrCl 50 to <80, and 2.32 for CrCl 30 to <50 in rivaroxaban-treated patients; 1.42 for CrCl ≥80, 2.45 for CrCl 50 to <80, and 2.77 for CrCl 30 to <50 in warfarin-treated patients).