Safety and Efficacy of Adjusted Dose of Rivaroxaban in Japanese Patients With Non-Valvular Atrial Fibrillation

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1 Circulation Journal Official Journal of the Japanese Circulation Society ORIGINAL ARTICLE Arrhythmia/Electrophysiology Safety and Efficacy of Adjusted Dose of Rivaroxaban in Japanese Patients With Non-Valvular Atrial Fibrillation Subanalysis of J-ROCKET AF for Patients With Moderate Renal Impairment Masatsugu Hori, MD, PhD; Masayasu Matsumoto, MD, PhD; Norio Tanahashi, MD; Shin-ichi Momomura, MD; Shinichiro Uchiyama, MD, PhD; Shinya Goto, MD, PhD; Tohru Izumi, MD, PhD; Yukihiro Koretsune, MD, PhD; Mariko Kajikawa, MD, PhD; Masaharu Kato; Hitoshi Ueda, PhD; Kazuya Iwamoto, MD, PhD; Masahiro Tajiri, BSc on behalf of the J-ROCKET AF study investigators Background: In the Japanese Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (J-ROCKET AF) study, rivaroxaban 15 mg once daily was given to patients with creatinine clearance (CrCl) 50 ml/min (preserved renal function), and was reduced to 10 mg once daily in patients with CrCl ml/min (moderate renal impairment). The aim of this subanalysis was to assess the safety and efficacy of the adjusted dose of rivaroxaban compared with warfarin in a cohort with moderate renal impairment. Methods and Results: Compared with patients with preserved renal function, those with moderate renal impairment (22.2% of all randomized patients) had higher rates of bleeding and stroke events irrespective of study treatment. Among those with moderate renal impairment, the principal safety endpoint occurred at 27.76%/year with rivaroxaban vs %/year with warfarin (hazard ratio [HR], 1.22; 95% confidence interval [CI]: ) and the rate of the primary efficacy endpoint was 2.77%/year vs. 3.34%/year (HR, 0.82; 95% CI: ), respectively. There were no significant interactions between renal function and study treatment in the principal safety and the primary efficacy endpoints (P=0.628, for both interactions, respectively). Conclusions: The safety and efficacy of rivaroxaban vs. warfarin were consistent in patients with moderate renal impairment and preserved renal function. (Circ J 2013; 77: ) Key Words: Atrial fibrillation; Renal impairment; Rivaroxaban; Stroke; Atrial fibrillation (AF) is the most common cardiac rhythm disorder and is associated with an increased risk of ischemic stroke and thromboembolism. 1 has been widely used as the most effective anti-thrombotic therapy for stroke prevention in patients with AF 2 and has the advantage that it can be dose-adjusted according to the patient s risk for bleeding and thromboembolism. The use of warfarin, however, has many limitations, including multiple food and drug interactions, a narrow therapeutic window, the need for frequent coagulation status monitoring, and an increased risk of bleeding events. 2 6 In an attempt to overcome these drawbacks, new anticoagulants, which are effective, safe, Received July 18, 2012; revised manuscript received September 25, 2012; accepted October 26, 2012; released online December 8, 2012 Time for primary review: 19 days Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka (M.H.); Institute for Clinical Research, Osaka National Hospital, Osaka (Y.K.); Bayer Yakuhin, Osaka (M. Kajikawa, M. Kato, H.U., K.I., M.T.); Department of Clinical Neuroscience and Therapeutics, Hiroshima University, Hiroshima (M.M.); Department of Neurology, Saitama Medical University International Medical Center, Saitama (N.T.); Division of Cardiovascular Medicine, Saitama Medical Center, Jichi Medical University, Saitama (S.M.); Department of Neurology, Tokyo Women s Medical University, Tokyo (S.U.); Department of Medicine (Cardiology), Tokai University School of Medicine, Tokyo (S.G.); and Department of Cardio-angiology, Kitasato University School of Medicine, Sagamihara (T.I.), Japan Clinical Trial Registration: NCT This paper was presented at the 76 th Annual Scientific Meeting of the Japanese Circulation Society, Late Breaking Clinical Trials. Mailing address: Masatsugu Hori, MD, PhD, Osaka Medical Center for Cancer and Cardiovascular Diseases, Nakamichi, Higashinariku, Osaka , Japan. hori-ma@mc.pref.osaka.jp ISSN doi: /circj.CJ All rights are reserved to the Japanese Circulation Society. For permissions, please cj@j-circ.or.jp

2 Rivaroxaban in AF Patients With Renal Impairment 633 Statistical Analysis The primary objective of J-ROCKET AF was to test whether rivaroxaban was non-inferior to warfarin with respect to principal safety outcome in the safety group, which included all patients who received 1 dose of the investigational drug, on treatment, which was defined as the period from the first dose of study drug up to 2 days after the last dose, as evaluated on Cox proportional hazard modeling. In this subanalysis, rivaroxaban-treated patients were divided according to dose, 10 mg or 15 mg based on CrCl at baseline. Event rates by treatment arm and renal function group are presented as %/year. The homogeneity of treatment effects across renal dysfunction status (30 49 ml/min and 50 ml/min) regarding the occurrence of principal safety and primary efficacy endpoints was tested based on the Cox model including treatment group, renal dysfunction status and their interaction. Point estimates and 95% confidence intervals (CI) for hazard ratio (HR) for rivaroxaban vs. warfarin, within levels of renal dysfunction based on the previous model are presented in the safety group, on-treatment for the safety endpoints, and in the per-protocol group, on-treatment for the efficacy endand convenient to use, have been developed and tested in recent clinical trials. 7,8 Editorial p 596 Rivaroxaban is a novel oral direct factor Xa inhibitor, with a once-daily fixed dose, and is expected to provide more consistent and predictable anticoagulation effects than warfarin The Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) ROCKET AF study was an international multicenter study comparing rivaroxaban 20 mg once daily with warfarin for the prevention of stroke and systemic embolism in 14,264 patients with AF. 12 Rivaroxaban was non-inferior to warfarin even on intention-to-treat analysis for the prevention of stroke and systemic embolism, and the superiority of rivaroxaban over warfarin while patients were receiving investigational drugs was demonstrated. There was no significant difference in either the composite of major and non-major clinically relevant bleeding or in the individual components of the composite endpoint. Fewer cases of intracranial hemorrhage were observed with rivaroxaban compared with warfarin, with fewer fatal bleeding events. In the global ROCKET AF study, 20 mg once-daily rivaroxaban was selected for patients with creatinine clearance (CrCl) 50 ml/min. 12 (CrCl was determined by the Cockcroft- Gault formula. 13 ) Kubitza et al reported that in patients with moderate renal impairment (CrCl ml/min), the maximum serum concentration of rivaroxaban was 25 30% higher than in healthy controls 14 and pharmacokinetic models projected that a 25% dose reduction would lead to similar exposure and trough levels in patients with moderate renal impairment. 15 Therefore, patients with moderate renal impairment were treated with an adjusted dose of rivaroxaban (15 mg once daily) to adjust exposure in the global ROCKET AF study. In Japan, based on pharmacokinetic data indicating that rivaroxaban exposure in Japanese patients receiving a 15-mg oncedaily dose is comparable to that in Caucasian patients receiving a 20-mg once-daily dose, 16 a separate study, J-ROCKET AF, was conducted comparing a Japan-specific adjusted dose of rivaroxaban with an adjusted dose of warfarin in patients with AF. In the J-ROCKET AF study, 15 mg rivaroxaban once daily was used for patients with CrCl 50 ml/min and a further reduced dose (10 mg rivaroxaban once daily) was used for Japanese patients with moderate renal impairment. Non-inferiority of rivaroxaban as opposed to warfarin in terms of the principal safety endpoint (major or non-major clinically relevant bleeding) was demonstrated. The present subanalysis assessed the risks and benefits of this adjusted dose of rivaroxaban compared with warfarin in a high-risk cohort of patients with moderate renal impairment and examined the validity of the dose setting of rivaroxaban 10 mg once daily for patients with moderate renal impairment. Methods Study Design, Participants and Procedure The design and main results of the J-ROCKET AF study have been reported previously. 17 In brief, this was a prospective, randomized, double-blind, double-dummy, parallel-group, active-controlled, multicenter clinical trial comparing the safety of rivaroxaban (15 mg once daily in patients with CrCl 50 ml/min or 10 mg once daily in patients with CrCl ml/min at baseline) vs. dose-adjusted warfarin, in accordance to Japanese guidelines for patients with non-valvular AF. The trial was conducted in accordance with Japanese Good Clinical Practice. The study was approved by the Institutional Review Boards and all patients provided their informed consent. Japanese patients aged 20 years with non-valvular AF, documented electrocardiographically 30 days before enrollment, were randomized at 167 participating facilities in Japan. Patients had a history of prior ischemic stroke, transient ischemic attack, or non-central nervous system (non-cns) systemic embolism, or had 2 of the following risk factors for thromboembolism: congestive heart failure and/or left ventricular ejection fraction 35%, hypertension, age 75 years, or diabetes mellitus. Patients with CrCl <30 ml/min were excluded. Randomization of patients without prior stroke, transient ischemic attack, or non-cns systemic embolism and with only 2 stroke risk factors was limited to 10% of the total number of target patients. Patients were randomized to receive either oral rivaroxaban 15 mg once daily (10 mg once daily in patients with CrCl ml/min at randomization) or dose-adjusted warfarin to a target international normalized ratio (INR) of in patients aged <70 years or a reduced target INR of in patients aged 70 years. The pre-specified maximum exposure period was 30 months. At the end-of-study visit (or at an early discontinuation visit) patients were transitioned from study medication to open-label commercial warfarin or other appropriate therapy by the investigator according to usual clinical practice. Follow-up was completed at the follow-up visit performed 30 days after the end-of-study visit or early discontinuation visit. Outcomes An independent clinical endpoint committee adjudicated all suspected strokes, systemic embolisms, myocardial infarctions, deaths, and bleeding events that contributed to pre-specified endpoints. The principal safety endpoint was a composite of major and non-major clinically relevant bleeding. Bleeding events involving the CNS that satisfied the definition of stroke were classified as hemorrhagic strokes and were included in both the principal safety and the primary efficacy endpoints. Adverse events (AEs) were also assessed. The primary efficacy endpoint was the composite of adjudicated all stroke (ischemic or hemorrhagic) and non-cns systemic embolism.

3 634 HORI M et al. Table 1. Baseline Patient Characteristics Characteristic Rivaroxaban 10 mg o.d. (n=141) CrCl ml/min (n=143) Rivaroxaban 15 mg o.d. (n=498) CrCl 50 ml/min (n=496) Age (years) 78 (74 81) 78 (75 82) 70 (64 75) 70 (65 75) Female Body weight (kg) 56.0 ( ) 56.1 ( ) 65.5 ( ) 66.0 ( ) SBP (mmhg) 129 ( ) 126 ( ) 130 ( ) 130 ( ) Paroxysmal AF Prior ASA use Prior VKA use CHADS2 score (mean) Prior stroke/tia or systemic embolism Congestive heart failure Hypertension Diabetes mellitus Prior myocardial infarction Data given as median (IQR) or %. ASA, acetylsalicylic acid; CHADS2, a clinical prediction rule for estimating the risk of stroke for patients with atrial fibrillation, it was calculated by assigning 1 point for diagnoses of congestive heart failure, hypertension, age 75 years or older, and diabetes mellitus and 2 points for prior stroke or transient ischemic attack; CrCl, creatinine clearance; o.d., once daily; SBP, systolic blood pressure; TIA, transient ischemic attack; VKA, vitamin K antagonist. points. Statistical analysis was performed by Bayer Yakuhin using SAS version 9.1 (SAS Institute, Cary, NC, USA). Results Patient Characteristics Baseline patient characteristics randomized to rivaroxaban or warfarin are given in Table 1. Of the 1,278 patients in the safety group, 284 (22.2%) had moderate renal impairment (CrCl ml/min). The median age was 78 years in those with moderate renal impairment and 70 years in those with preserved renal function (CrCl 50 ml/min). The proportion of women was higher in the moderate renal impairment group compared to the preserved renal function group. In addition, patients with moderately impaired renal function had lower body weight and higher CHADS2 scores than those with preserved renal function. Safety Outcomes The overall primary safety analysis for J-ROCKET AF showed that a composite of major bleeding and non-major clinically relevant bleeding events occurred in 138 patients on rivaroxaban (18.04%/year) and in 124 on warfarin (16.42%/ year; HR: 1.11; 95% CI: ). In this subanalysis, the principal safety endpoint occurred more frequently in those with moderate renal impairment than in those with preserved renal function, regardless of randomized treatment assignment (Figure 1A). In patients with moderate renal impairment, the primary safety outcome occurred in 27.76%/year with rivaroxaban 10 mg once daily vs %/year with warfarin (HR, 1.22; 95% CI: ). In those with preserved renal function, it occurred in 15.64%/year vs %/year (HR, 1.07; 95% CI: ), respectively. No significant interaction between those with moderate renal impairment and those with preserved renal function (P=0.628 for interaction) was observed (Figure 1B). Furthermore, in patients with moderate renal impairment, major bleeding occurred in 5.09%/year with rivaroxaban vs. 5.63%/year with warfarin (HR, 0.89; 95% CI: ). In those with preserved renal function, major bleeding occurred in 2.47%/year with rivaroxaban vs. 3.04%/year in warfarin (HR, 0.82; 95% CI: ). Both renal status groups behaved similarly (P=0.858 for interaction). Critical organ bleeding occurred in 1.68%/year with rivaroxaban vs. 2.80%/ year with warfarin (HR, 0.59; 95% CI: ) in the moderate renal impairment patients. In those with preserved renal function, critical organ bleeding occurred in 1.44%/year with rivaroxaban vs. 1.21%/year with warfarin (HR, 1.21; 95% CI: ). Although HR differed between subgroups based on renal function, there was no significant interaction in critical organ bleeding (P=0.420 for interaction). Also, there were no interactions between these 2 subgroups in other types of bleeding (Figure 1B). With regard to bleeding that occurred at critical sites in patients with moderate renal impairment, intracranial hemorrhage occurred in 2 patients (1.42%) with rivaroxaban and in 4 patients (2.80%) with warfarin. In patients with preserved renal function, intracranial hemorrhage occurred in 3 patients (0.60%) with rivaroxaban and in 6 patients (1.21%) with warfarin (Figure 2). There was a tendency toward fewer cases of intracranial hemorrhage in the rivaroxaban group than in the warfarin group regardless of renal function. AEs Table 2 lists the 10 most frequent AEs observed in the rivaroxaban-treated patients. Epistaxis and gingival bleeding were more frequent in the rivaroxaban group than in the warfarin group irrespective of renal function. Efficacy Outcomes The primary efficacy analysis for overall J-ROCKET AF showed that the composite of adjudicated all stroke and non- CNS systemic embolism occurred in 11 patients on rivaroxaban (1.26%/year) and in 22 on warfarin (2.61%/year; HR, 0.49; 95% CI: ). As shown in Figure 3, in patients with moderate renal impairment, the primary efficacy endpoint occurred in 2.77%/year with rivaroxaban 10 mg once daily vs.

4 Rivaroxaban in AF Patients With Renal Impairment 635 Figure 1. Safety outcomes according to treatment group and renal function; safety group, on treatment. (A) Kaplan-Meier curve of time until first major bleeding or non-major clinically relevant bleeding event. (B) Components of the principal safety outcomes: major and non-major clinically relevant bleeding. *Major or non-major clinically relevant bleeding. Rivaroxaban 15 mg once daily. Rivaroxaban 10 mg once daily. CI, confidence interval; CrCl, creatinine clearance; PRBC, packed red blood cells. 3.34%/year with warfarin (HR, 0.82; 95% CI: ), and in 0.87%/year with rivaroxaban 15 mg once daily vs. 2.41%/ year with warfarin in those with preserved renal function (HR, 0.36; 95% CI: ). The primary efficacy endpoint occurred more frequently in patients with moderate renal impairment than in those with preserved renal function irrespective of study treatment. When compared between the 2 treatment groups, the rate of primary efficacy endpoint was lower in the rivaroxaban group than in the warfarin group irrespective of renal function. Although HR was numerically

5 636 HORI M et al. Figure 2. Bleeding sites of major bleeding according to renal function; safety group, on treatment. CrCl, creatinine clearance; GI, gastrointestinal. Table 2. Primary Adverse Events vs. Renal Function Adverse event (%) Rivaroxaban 10 mg o.d. (n=141) CrCl ml/min (n=143) Rivaroxaban 15 mg o.d. (n=498) CrCl 50 ml/min (n=496) Nasopharyngitis Epistaxis Subcutaneous hemorrhage Contusion Diarrhea URTI Gingival bleeding Back pain Diabetes mellitus Cardiac failure Ten most frequent adverse events observed in the rivaroxaban-treated patients. CrCl, creatinine clearance; o.d., once daily; URTI, upper respiratory tract inflammation. emic stroke and systemic embolism in AF patients. 19,20 In contrast, renal impairment is a risk factor for bleeding during anti-thrombotic therapy , the current standard anticoagulant for prevention of stroke in AF patients, is used with adjusted dose according to its pharmacodynamics (PD) parameter, prothrombin time-international normalized ratio (PT-INR). In the guidelines, the same target PT-INR is applied regardless of renal function. 3,24 That is to say, the current anticoagulant therapy for renally impaired AF patients is based on the concept of obtaining similar anticoagulation status by PD adjusted dose to that of patients with preserved renal funcdifferent between patients with moderate renal impairment and those with preserved renal function, there was no significant interaction (P=0.279 for interaction). Discussion Among patients with AF, renal impairment is common and progressively worsens with advancing age. Such patients have a greater prevalence of thromboembolic risk factors (eg, hypertension, diabetes) than the general population. 18 Renal impairment is also known to be an independent risk factor for isch-

6 Rivaroxaban in AF Patients With Renal Impairment 637 Figure 3. Efficacy according to treatment group and renal function; per-protocol group, on treatment. *Stroke plus non-cns systemic embolism. Rivaroxaban 15 mg once daily. Rivaroxaban 10 mg once daily. CI, confidence interval; CrCl, creatinine clearance. tion. The net effect of anticoagulation in patients with renal impairment is still not well understood and there is no consensus on the optimal balance between risk and benefit of the therapy. Novel anticoagulants, however, which have become available in this clinical setting recently, should provide at least comparable net effect to that of current standard treatment warfarin. Novel oral anticoagulants have stable and predictive pharmacokinetic and PD profiles, do not require routine coagulation monitoring and are fixed-dose formulations. 8,25 But the doses of novel oral anticoagulants also should be adjusted to maintain the balance between efficacy and safety. While rivaroxaban is predominantly metabolized by the liver, approximately one-third is cleared renally. 9,10 Therefore, renal clearance of rivaroxaban is anticipated to decrease with increasing renal impairment. 14 We estimated rivaroxaban exposure based on the differences in CrCl, a marker for renal function. In the global ROCKET-AF study and the Japanese-specific J-ROCKET AF study, the dose of rivaroxaban was set at 20 mg once daily and 15 mg once daily respectively for patients with preserved renal function, and at 15 mg once daily and 10 mg once daily respectively for those with moderate renal impairment. The key concept of the dose schedule was to keep the exposure of rivaroxaban comparable in each patient by adjusting the dose of rivaroxaban based on CrCl. CrCl was determined by the Cockcroft-Gault formula, 13 which takes into account the age, weight, sex and serum creatinine level of the patient. By keeping the exposure similar for each patient, the safety and efficacy of rivaroxaban, compared to warfarin, was expected to be maintained even in patients with moderate renal impairment who are at high risk of bleeding and thromboembolism. As a result of this subanalysis, compared with patients with preserved renal function, those with moderate renal impairment had higher rates of bleeding events irrespective of study treatment. In each subgroup divided by renal function, the rate of the principal safety endpoint was comparable between rivaroxaban and warfarin, showing no significant interaction between the 2 subgroups. The event rate of efficacy events was lower in the rivaroxaban group than in the warfarin group, although the number of cases was limited. Thus, adjusting the dose of rivaroxaban, originally a fixed- dose formulation, to 10 mg once daily according to CrCl was considered appropriate for achieving comparable efficacy to warfarin without increasing the risk of bleeding. This validated the dose setting strategy to adjust rivaroxaban exposure. In addition, the results obtained in this subanalysis of the J-ROCKET AF study are consistent with those reported in the subgroup analysis of the global ROCKET AF study, 26 as the primary analysis of the J-ROCKET AF study was consistent with that of the global ROCKET AF study. 12,17 This additionally validated the dose setting strategy of rivaroxaban. Study Limitations In general, patients with renal impairment have a greater prevalence of thromboembolic and bleeding risk factors (eg, high age and low body weight). Also in this subanalysis, patients with moderate renal impairment had a higher prevalence of those risk factors; the median age and body weight in the moderate renal impairment group were 78 years old and 56 kg, respectively, whereas in the preserved renal function group were 70 years old and 66 kg, respectively. J-ROCKET AF was not primarily designed to compare the safety and efficacy of rivaroxaban between patients with moderate impairment and those with preserved renal function. Consequently, these confounding factors may have affected the safety and efficacy outcome of this subanalysis in addition to renal function. Conclusion In this subanalysis of J-ROCKET AF, the safety and efficacy of rivaroxaban vs. warfarin were consistent in patients with moderate renal impairment and those with preserved renal function. The validity of the dose schedule of rivaroxaban 10 mg once daily for Japanese patients with moderate renal impairment is confirmed. Acknowledgments The rivaroxaban clinical development program is co-sponsored by Janssen Pharmaceuticals (Raritan, NJ, USA) and Bayer HealthCare Pharmaceuticals (Leverkusen, Germany). The trial was funded by the Bayer Healthcare Pharmaceuticals Japanese subsidiary, Bayer Yakuhin. Drs Iwamoto, Kajikawa and Ueda, and Mr Tajiri and Mr Kato report employment by Bayer Yakuhin. Dr Hori received consultation fees from Bayer, Boehringer

7 638 HORI M et al. Ingelheim, Bristol Myers-Squibb and Pfizer. Dr Matsumoto and Dr Momomura received consultation fees from Bayer. Dr Tanahashi received consultation fees from Bayer and Mitsubishi Tanabe, and gratuities from Mitsubishi Tanabe and Sanofi-Aventis. Dr Goto received research grants from Astellas, AstraZeneca, Daiichi, Eisai, Kowa, Ono, Otsuka, Pfizer, Sanofi-Aventis, and Takeda, and gratuities from Daiichi-Sankyo, Eisai, Otsuka, Sanofi-Aventis and Schering-Plough. Dr Izumi received consultation fees from Bayer and Pfizer. Dr Koretsune received gratuities from Bayer, Boehringer Ingelheim, Daiichi-Sankyo and Bristol Myers-Squibb. Dr Uchiyama received consultation fees from Bayer and Boehringer Ingelheim and research grants from Bayer, Boehringer Ingelheim and Daiichi-Sankyo. No other conflicts of interest are reported. References 1. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: The Framingham Study. Stroke 1991; 22: Hart RG, Pearce LA, Aguilar MI. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007; 146: Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006; 114: e257 e Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363: Ezekowitz MD, Connolly S, Parekh A, Reilly PA, Varrone J, Wang S, et al. Rationale and design of RE-LY: Randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. Am Heart J 2009; 157: , 810 e1 e2. 7. Hori M, Connolly SJ, Ezekowitz MD, Reilly PA, Yusuf S, Wallentin L; RE-LY Investigators. Efficacy and safety of dabigatran vs. warfarin in patients with atrial fibrillation: Sub-analysis in Japanese population in RE-LY trial. Circ J 2011; 7: Ogawa S, Koretsune Y, Yasaka M, Aizawa Y, Atarashi H, Inoue H, et al. Antithrombotic therapy in atrial fibrillation: Evaluation and positioning of new oral anticoagulant agents. Circ J 2011; 75: Kubitza D, Becka M, Roth A, Mueck W. Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin 2008; 24: Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M. Safety, pharmacodynamics, and pharmacokinetics of BAY an oral, direct Factor Xa inhibitor after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 2005; 61: Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY , an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 2005; 78: Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: Kubitza D, Becka M, Mueck W, Halabi A, Maatouk H, Klause N, et al. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol 2010; 70: Mueck W, Lensing AW, Agnelli G, Decousus H, Prandoni P, Misselwitz F. Rivaroxaban: Population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet 2011; 50: Tanigawa T, Kaneko M, Hashizume K, Kajikawa M, Ueda H, Tajiri M, et al. Model-based dose selection for phase III rivaroxaban study in Japanese patients with non-valvular atrial fibrillation. Drug Metab Pharmacokinet 2012 July 17 [Epub ahead of print]. 17. Hori M, Matsumoto M, Tanahashi N, Momomura S, Uchiyama S, Goto S, et al. Rivaroxaban versus warfarin in Japanese patients with atrial fibrillation. Circ J 2012; 76: Whaley-Connell AT, Sowers JR, Stevens LA, McFarlane SI, Shlipak MG, Norris KC, et al. CKD in the United States: Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) Am J Kidney Dis 2008; 51: S13 S Go AS, Fang MC, Udaltsova N, Chang Y, Pomernacki NK, Borowsky L, et al. Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: The anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Circulation 2009; 119: Friberg L, Rosenqvist M, Lip GY. Evaluation of risk stratification schemes for ischaemic stroke and bleeding in patients with atrial fibrillation: The Swedish Atrial Fibrillation cohort study. Eur Heart J 2012; 33: Fang MC, Go AS, Chang Y, Borowsky LH, Pomernacki NK, Udaltsova N, et al. A new risk scheme to predict warfarin-associated hemorrhage: The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study. J Am Coll Cardiol 2011; 58: Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: The Euro Heart Survey. Chest 2010; 138: Vazquez E, Sanchez-Perales C. The HAS-BLED score and renal failure. Chest 2011; 139: ; author reply Ogawa S, Hori M. Urgent statement on antithrombotic therapy of atrial fibrillation. Circ J 2011; 75: Schirmer SH, Baumhakel M, Neuberger HR, Hohnloser SH, van Gelder IC, Lip GY, et al. Novel anticoagulants for stroke prevention in atrial fibrillation: Current clinical evidence and future developments. J Am Coll Cardiol 2010; 56: Fox KA, Piccini JP, Wojdyla D, Becker RC, Halperin JL, Nessel CC, et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J 2011; 32: