Response by Fordyce et al to Letter Regarding Article, “On-Treatment Outcomes in Patients With Worsening Renal Function With Rivaroxaban Compared With Warfarin: Insights From ROCKET AF”
Authors: Christopher B. Fordyce, Jonathan P. Piccini, Manesh R. Patel
Journal: Circulation (2016)

In Response:We appreciate the letter by Escober et al that highlights the fact that there was a greater temporal decline in renal function among patients taking warfarin than among those taking rivaroxaban from the ROCKET-AF trial (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation). 1 They assert that warfarin-related nephropathy contributes to worsening renal function on the basis of glomerular microbleeds and renal tubular obstruction and suggest that perhaps a novel anticoagulant such as rivaroxaban may be relatively more protective than warfarin in this setting.However, the results of our study should be interpreted with caution.First, the incidence of anticoagulant-related nephropathy is difficult to determine because observational studies that have examined its incidence have relied on a presumptive diagnosis of anticoagulant-related nephropathy rather than a biopsy-defined diagnosis. 2,3Second, in our ROCKET-AF substudy, although patients in the warfarin arm had a statistically significant decline in glomerular filtration rate in comparison with those taking rivaroxaban, this difference was small (0.8 mL/min) and occurred over a relatively long period of time, because the median follow-up duration in this substudy was 641 days.Third, we found no significant difference in the proportion of patients experiencing worsening renal function (>20% decline in renal function) who were taking rivaroxaban (26%) in comparison with warfarin (27%, P=0.09).Therefore, the clinical significance of this greater reduction in creatine clearance among patients receiving warfarin is unclear.Our results are also not entirely consistent with recent novel anticoagulant substudies that have evaluated renal function.A RE-LY trial (Randomized Evaluation of Long Term Anticoagulant Therapy [RE-LY] With Dabigatran Etexilate) analysis found that patients exhibit a decline in renal function over time that appears to be greater in those taking warfarin (-3.68 mL/min) in comparison with dabigatran (-2.46 mL/ min for the 150 mg twice daily dose at 30 months). 4 In contrast, an ARISTOTLE substudy (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) found that renal function declined significantly more rapidly in the apixaban group (-1.42 mL/min) in comparison with warfarin (-0.92) at 12-month followup. 5Perhaps most important is that renal function declines in the overall population in each of the 3 trials among patients with nonvalvular atrial fibrillation, irrespective of the anticoagulant used.Therefore, although future studies are required to truly elucidate whether a potential nephroprotective effect of rivaroxaban or other novel anticoagulant exists over warfarin, we do agree with Escober et al that patients who receive anticoagulation should have their renal function monitored routinely.