Reconsideration of Anticoagulant Therapy in Japanese Patients With Atrial Fibrillation and Moderate Renal Impairment

on bleeding risk in Japanese patients receiving warfarin. Will New Oral Anticoagulants Offer a Benefit to Japanese AF Patients With Moderate Renal Impairment?The new oral anticoagulants (dabigatran, rivaroxaban and apixaban) have been recently reported as associated with stroke rates that are lower than or comparable to that for warfarin, and all these anticoagulants have shown reduced intracranial hemorrhage compared with warfarin.7-9 These 3 new drugs are mainly or partially eliminated by the kidneys (dabigatran 80%, rivaroxaban 33%, apixaban 25%).Patients with a creatinine clearance (ClCr) <30 ml/min (<25 ml/min in the ARISTOTLE trial) were excluded from large prospective phase III clinical trials.In the RE-LY trial, 19% of participants had moderate renal impairment (ClCr 30-49 ml/min).Despite a 2.3-fold increase in the steady-state trough concentration of dabigatran compared with patients with normal renal function, patients with moderate renal function showed a greater stroke reduction when taking dabigatran 150 mg twice daily compared with warfarin (hazard ratio 0.46, 95% confidence interval [CI] 0.29-0.73).10 Furthermore, the risk for major bleeding was comparable to that of warfarin (hazard ratio 0.97, 95% CI 0.74-1.27).10 Therefore, the FDA approved dabigatran with no dose adjustment for patients with a ClCr of 30-49 ml/min.However, there are no appropriate clinical data for Japanese patients.Subanalyses of the ROCKET AF and ARISTOTLE trials indicated that moderate renal impairment was associated with increased risk of stroke/systemic thromboembolism and bleeding, and that rivaroxaban or apixaban did not increase the risk of major bleeding (including intracranial hemorrhage) in AF patients with moderate renal impairment.11,12 Pharmacokinetic modeling of the steady-state of rivaroxaban indicated that 15 mg once daily for Japanese patients would be a comparable exposure to 20 mg once daily in Caucasian patients.The J-ROCKET AF study was conducted entirely in Japan to evaluate the safety of 15 mg once daily of rivaroxaban and of 10 mg of rivaroxaban once daily in patients with a ClCr of 30-49 ml/min compared with warfarin dosed according to Japanese guidelines.13 The results of the J-ROCKET AF study were consistent with the global ROCKET-AF trial.