Net Clinical Benefit of Rivaroxaban versus Warfarin in Japanese Patients with Nonvalvular Atrial Fibrillation: A Subgroup Analysis of J-ROCKET AF Shinichiro Uchiyama, MD, PhD,* Masatsugu Hori, MD, PhD,† Masayasu Matsumoto, MD, PhD,‡ Norio Tanahashi, MD, PhD,x Shin-ichi Momomura, MD,jj Shinya Goto, MD, PhD,{ Tohru Izumi, MD, PhD,# Yukihiro Koretsune, MD, PhD,** Mariko Kajikawa, MD, PhD,†† Masaharu Kato, MSc,†† Hitoshi Ueda, PhD,†† Kazuma Iekushi, MD, PhD,†† Satoshi Yamanaka, MD, PhD,†† and Masahiro Tajiri, BSc,†† on behalf of the J-ROCKET AF Study Investigators

Background: The risk factors that have been identified for bleeding events with rivaroxaban are predominantly the same as those predicting thromboembolic ones in patients with atrial fibrillation (AF). Our aim was to determine the net clinical benefit (NCB) from the results of the J-ROCKET AF trial, in which rivaroxaban was compared with warfarin in Japanese patients with AF. Methods: Two strategies were adopted to quantify the NCB. First, the NCB was calculated as the number of ischemic strokes avoided with anticoagulation minus the number of excess intracranial hemorrhage (ICH) with a weight of 1.5. Second, the composite end point of major bleeding events and secondary efficacy end points (stroke, noncentral nervous system systemic embolism, myocardial infarction and death) to ascertain the NCB were established. Subgroup analysis by CHADS2 score or creatinine clearance was also performed. Results: The adjusted NCB, which was given a weight of 1.5 for ICH, was nominally significant in favor of rivaroxaban therapy (difference in incidence rate 22.13; 95% confidence interval [CI]: 2.26 to 23.99). Furthermore, the event rate of the composite end point tended to be lower in patients treated with rivaroxaban than in those treated with warfarin (rivaroxaban: 4.97% per

From the *Department of Neurology, Tokyo Women’s Medical University, Tokyo; †Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka; ‡Department of Clinical Neuroscience and Therapeutics, Hiroshima University, Hiroshima; xDepartment of Neurology, Saitama Medical University International Medical Center, Saitama; jjDivision of Cardiovascular Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan; {Department of Medicine (Cardiology), Tokai University School of Medicine, Tokyo; #Department of Cardio-angiology, Kitasato University School of Medicine, Sagamihara City, Kanagawa; **Institute for Clinical Research, Osaka National Hospital, Japan; and ††Bayer Yakuhin Ltd, Osaka, Japan. Received September 30, 2013; accepted October 2, 2013. The rivaroxaban clinical development program is cosponsored by Janssen Pharmaceuticals, Inc. (Raritan, NJ) and Bayer HealthCare Pharmaceuticals AG (Leverkusen, Germany). The trial was funded by Bayer Healthcare Pharmaceuticals AG’s Japanese subsidiary, Bayer Yakuhin Ltd. Disclosures: S.U. has received consultancy fees from Bayer and Boehringer Ingelheim and research grants from Bayer, Boehringer

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Ingelheim, and Daiichi-Sankyo. M.H. has received consultancy fees from Bayer, Boehringer Ingelheim, Bristol Myers-Squibb, and Pfizer. M.M. and S.-I.M. have received consultancy fees from Bayer. N.T. has received consultancy fees from Bayer and Mitsubishi Tanabe and honoraria from Mitsubishi Tanabe and Sanofi-Aventis. S.G. has received research grants from Astellas, AstraZeneca, Daiichi, Eisai, Kowa, Ono, Otsuka, Pfizer, Sanofi-Aventis, and Takeda and honoraria from Daiichi-Sankyo, Eisai, Otsuka, Sanofi-Aventis, and ScheringPlough. T.I. has received consultancy fees from Bayer and Pfizer. Y.K. has received honoraria from Bayer, Boehringer Ingelheim, Daiichi-Sankyo, and Bristol Myers-Squibb. K.I., S.Y., M.K., H.U., M.T., and M.K. report employment by Bayer Yakuhin. No other conflicts of interest are reported. Address correspondence to Shinichiro Uchiyama, MD, PhD, Department of Neurology, Tokyo Women’s Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.10.001

Journal of Stroke and Cerebrovascular Diseases, Vol. 23, No. 5 (May-June), 2014: pp 1142-1147

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year, warfarin: 6.11% per year; difference in incidence rate: 21.14; 95% CI: 23.40 to 1.12). The event rate of the composite end point tended to be consistently low in patients treated with rivaroxaban in the subanalysis by CHADS2 score and renal function. Conclusion: Analysis of the NCB supports that rivaroxaban therapy provides clinical benefit for Japanese patients with AF. Key Words: Atrial fibrillation—oral anticoagulation—stroke prevention—net clinical benefit. Ó 2014 by National Stroke Association

Introduction Patients with atrial fibrillation (AF) are known to have a risk for ischemic stroke (IS) that is 4-5 times higher than in unaffected subjects.1 AF is a very common cardiac arrhythmia, with a prevalence of 5%-15% at 80 years,2 and the number of patients with AF is continuing to increase. Until recent years, warfarin was the only oral anticoagulant drug clinically available that could effectively reduce the risk of stroke and non-central nervous system (CNS) systemic embolism. Recently, novel oral anticoagulant drugs have been developed as anticoagulant options for the treatment of patients with AF. These novel drugs have the potential to address some of the limitations of warfarin.3 One such novel oral anticoagulant is rivaroxaban, which inhibits thrombus formation by directly inhibiting Factor Xa, which plays a central role in the coagulation cascade.3-5 Rivaroxaban provides various benefits associated with its mechanism of action, which is different from that of warfarin. These benefits include rapid onset of action, no need to conduct monitoring for dose adjustment, and fewer interactions with concomitant drugs and food containing vitamin K. Although various risk stratification methods for patients with AF have been reported on the basis of risk factors identified in clinical studies and cohort studies, the balance between the risk of IS and the risk of bleeding has not extensively been investigated in patients with AF. One of the most widely used methods of risk assessment for stroke is the CHADS2 score.6 However, the CHA2DS2-VASc score has been recommended recently to compensate for deficiencies in the CHADS2 score.7 Additionally, the site of bleeding influences the prognosis of the patients, and intracranial hemorrhage (ICH) is the most devastating bleeding complication with anticoagulant therapy. In the J-ROCKET AF trial, a large clinical study in Japanese patients, the rivaroxaban group showed a lower event rate of intracranial bleeding and noninferiority in the event rate of major bleeding compared with the warfarin group.8 Recently, revised international guidelines (European Society of Cardiology9) and local guidelines (Canadian Cardiovascular Society10) recommend the use of the HAS-BLED11 score to assess the risk of bleeding events. The principle aim of anticoagulation therapy is to optimize the balance between the risk of IS and the risk of bleeding events in patients with AF. Several methods for determining net

clinical benefit (NCB) have been proposed12: on the most simplistic level, Singer et al proposed to quantify NCB as the balance between the combined risks of IS and ICH and the use of anticoagulant therapy in patients with AF.13 The NCB of traditional warfarin therapy in patients with AF has already been reported using the method of Singer et al14; in contrast, the NCB of rivaroxaban has not yet been evaluated in Japanese patients. Additionally, to clarify the clinical benefit of rivaroxaban in specific population, such as with CHADS2 score, and with renal function, we also employed the first composite end point, initially designed in the J-ROCKET AF trial. We compared the NCB of rivaroxaban to that of warfarin using data obtained from the J-ROCKET AF trial.

Subjects and Methods Study Design, Participants, and Procedure The design and results of J-ROCKET AF have been described previously.8 In brief, J-ROCKET AF was a prospective, randomized, double-blind, double-dummy, parallel-group, active-controlled, multicenter clinical trial comparing the safety of rivaroxaban with that of doseadjusted warfarin, in accordance with the Japanese guidelines for patients with nonvalvular AF. The trial was approved by the Institutional Review Boards, and all patients gave informed consent. The trial was conducted in accordance with the Japanese Good Clinical Practice. In all, 1280 Japanese patients aged 20 years or more with nonvalvular AF, documented electrocardiographically 30 days or less before enrollment, were randomized at 167 participating facilities in Japan. Patients had a history of prior IS, transient ischemic attack, or non-CNS systemic embolism or had 2 or more of the following risk factors for thromboembolism: congestive heart failure and/or left ventricular ejection fraction of 35% or less, hypertension (defined as use of antihypertensive medications for #6 months before the screening visit, persistent systolic blood pressure of .140 mm Hg or diastolic blood pressure of .90 mm Hg), age 75 years or more, or diabetes mellitus (a history of type 1 or type 2 diabetes mellitus or use of antidiabetic medications for #6 months before the screening visit). Randomization of patients without prior IS, 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.

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Patients with a creatinine clearance (CrCl) less than 30 mL/min were excluded. Patients were randomized to receive either oral rivaroxaban 15 mg once daily (10 mg once daily in patients with CrCl 30-49 mL/min at randomization) or dose-adjusted warfarin (adjusted to a target international normalized ratio of 2.0-3.0 in patients aged ,70 years or to a reduced target international normalized ratio of 1.6-2.6 in patients aged $70 years, according to the Japanese guideline15). The dose of rivaroxaban administered in J-ROCKET AF differed from that administered in ROCKET AF, the global phase III trial for the prevention of stroke and systemic embolism in patients with nonvalvular AF.16 This was because pharmacokinetic modeling data indicated that 15 mg rivaroxaban once-daily doses in Japanese patients with AF would yield exposures similar to the 20 mg once-daily dose in Caucasian patients with AF.17 The prespecified 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-ups of patients were completed at the follow-up visit performed 30 days after the end-of-study visit or early discontinuation visit.

Net Clinical Benefit The event rate (% per year) for the NCB was calculated by treatment group in the safety population. First, the event rate (% per year) for the NCB was calculated by treatment group based on the expression proposed by Singer et al.13 The weighted factor reflects the relative impact, in terms of death and disability, of an ICH while receiving warfarin versus an IS while not receiving warfarin.18 Singer et al assigned their weighting a factor of 1.5, reflecting outcomes in the anticoagulation and risk factors in atrial fibrillation study cohort.19,20 The number ICH events were then subtracted from the number of IS events avoided by rivaroxaban therapy: NCB 5 1.5 3 (ICHon rivaroxaban 2 ICHon warfarin) 2 (ISon warfarin 2 ISon rivaroxaban). Second, we employed the first composite end point using a simple mathematical equation, comprising the sum of the number of major bleeding events and the number of primary and secondary efficacy end points (stroke, non-CNS systemic embolism, death, and myocardial infarction) in the J-ROCKET AF trial. The difference for each event rate and its 95% confidence interval (CI) were calculated. Subgroup analysis by CHADS2 score or CrCl category was also conducted. Number needed to treat minus number needed to harm (NNT 2 NNH) was also used to calculate the inverse of the risk difference, where nominal statistical significance was achieved. A negative NNT – NNH number denotes the number of person-years of treatment with rivaroxa-

ban (instead of with warfarin) needed to prevent 1 additional harmful event (NNT); a positive number denotes the number of person-years of treatment with rivaroxaban (instead of with warfarin) needed to cause 1 additional harmful event (NNH). The 95% CI of the event rate was calculated based on the percentile bootstrap method with 1000 repetitions. The adjustment for multiple testing was not conducted in this study. This study was not intended to test the NCB of rivaroxaban, but evaluation of NCB while patients were on treatment was conducted in the safety population in an exploratory manner.

Results The NCB was calculated as the number of IS events avoided with anticoagulation minus the number of excess ICH with a weight of 1.5 to account for the generally increased morbidity associated with intracranial bleeding events. As shown in Figure 1, rivaroxaban was nominally significantly favorable over warfarin. A similar result was obtained in analyses conducted without weighting and with a weight of 2.0 in a sensitivity analysis. Second, Figure 2 shows the point estimate for benefit from treatment with rivaroxaban; however, there were no difference between warfarin and rivaroxaban (rivaroxaban: 4.97% per year, warfarin: 6.11% per year; difference in incidence rate, 21.14; 95% CI: 23.40 to 1.12). The result was similar to that obtained in an analysis of cardiovascular death with respect to a composite end point for allcause deaths (rivaroxaban: 4.85% per year, warfarin: 5.87% per year; difference in incidence rate, 21.02; 95% CI: 23.24 to 1.21). Additionally, analyses stratified by the CHADS2 score and renal function were performed on these data. Treatment with rivaroxaban had a consistently positive trend in NCB in patients with CHADS2 scores of 2 or more (Fig 3) and in patients with moderate renal insufficiency (Fig 4), but to note, there were no difference between warfarin and rivaroxaban.

Discussion In this subanalysis of the J-ROCKET AF trial, we expected the NCB of rivaroxaban versus warfarin using

Figure 1. Net clinical benefit of rivaroxaban: ischemic stroke versus weighted intracranial hemorrhage.

NET BENEFIT OF RIVAROXABAN IN J-ROCKET AF

Figure 2. Net clinical benefit of rivaroxaban: the composite end point in JROCKET AF patients. A composite end point termed net clinical benefit, comprising the second efficacy and end points and major bleeding, was prespecified in the per-protocol population, on-treatment analysis. The upper is the composite of all-cause death, stroke, MI, major bleeding, and non-CNS systemic embolism. The lower is the composite of cardiac death, stroke, MI, major bleeding, and non-CNS systemic embolism. Abbreviations: CI, confidence interval; CNS, central nervous system; MI, myocardial infarction; NNT, number needed to treat; NNH, number needed to harm.

2 different strategies. First, the adjusted NCB, which was given a weight of 1.5 for ICH, of rivaroxaban was nominally significantly favorable over warfarin. Second, in the event rate of the composite end point, rivaroxaban had a consistently favorable trend compared with that of warfarin in the subanalysis by CHADS2 score and renal function, but predominantly, there were no difference. The most significant aspect of this analysis was that it assessed the NCB of rivaroxaban and warfarin under dose-adjusted warfarin treatment specifically in Japanese patients, whose management under warfarin differs from that of European and American patients. The Japanese guidelines recommend controlling warfarin at lower doses than those recommended in the international guidelines. Considering this, these results showed a favorable trend of the NCB of rivaroxaban compared with that of warfarin in Japanese patients with AF.

Analysis with a Weight on Cerebral Bleeding The outcome of intracranial bleeding is devastating to the patient; therefore, a weight of 1.5 was used for the

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Figure 4. Net clinical benefit of rivaroxaban: the composite end point in J-ROCKET AF patients with CrCl greater than 50 mL/min, 50-80 mL/ min, and less than 80 mL/min. Abbreviations: CI, confidence interval; CrCl, creatinine clearance; NNH, number needed to harm; NNT, number needed to treat.

event rate of ICH.13 Additionally, using impact weights of 2.0 or 1.0 for the difference in rates of ICH between patients receiving warfarin or rivaroxaban does not change our estimates of NCB in Figure 4. The overall pattern of results was largely preserved, reflecting the greater importance of the positive NCB of rivaroxaban compared with warfarin in patients with AF. The major contributor to these results is a nominally significant lower event rate of stroke in the rivaroxaban group compared with the warfarin group in the J-ROCKET AF trial.8 The detailed mechanism of this is unknown to date. Future elucidation of this mechanism is expected to further clarify the differences between rivaroxaban and warfarin. Insufficiently controlled hypertension, renal dysfunction, and hepatic dysfunction are regarded as component factors of HAS-BLED, the most popular score currently used for the assessment of bleeding risk. These factors were included in the exclusion criteria of the J-ROCKET AF trial. Because it is assumed that rivaroxaban will be administered to patients with these conditions in clinical practice, we consider that the NCB can promote the proper use of rivaroxaban. In Japan, postmarketing surveillance of rivaroxaban is being conducted, with the planned number of enrolled patients set at 10,000. Accumulation of safety and efficacy data in Japanese patients in this surveillance is anticipated to show the measures to further increase the NCB of rivaroxaban in patients with AF.

The CHADS2 Score

Figure 3. Net clinical benefit of rivaroxaban: the composite end point in JROCKET AF patients by CHADS2 score. Abbreviations: CI, confidence interval; CNS, central nervous system; NNH, number needed to harm; NNT, number needed to treat.

The CHADS2 score is a simple and widely used tool for the risk assessment of stroke. According to the original validation article published in 2001, CHADS2 scores are classified as follows: 0 5 low risk, 1-2 5 moderate risk, and 3 or more 5 high risk.6 The patients in the J-ROCKET AF trial were high-risk patients, with a mean CHADS2 score of 3.25. In the subanalysis stratified by CHADS2 score, rivaroxaban showed a marginally favorable trend of the NCB of rivaroxaban compared with that of

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warfarin in each patient group with a CHADS2 score of 2-5, though there were no difference between warfarin and rivaroxaban. Additionally, in the assessment of NCB in the modeling analysis based on a Danish nationwide cohort study, the benefits of treatment with novel oral anticoagulant drugs, including rivaroxaban, were greater than those of warfarin treatment for all CHADS2 scores, including patients with a CHADS2 score of 1, who were not included in this trial.21 However, benefits were not clear in low-risk patients with AF, even with warfarin treatment. We consider that the future identification of the NCB of rivaroxaban in low-risk patients with AF will help to clarify further the differences between rivaroxaban and warfarin. To achieve this, we need to accumulate clinical evidence in low-risk patients.

Renal Dysfunction Renal dysfunction is known to increase the risk not only for IS but also for intracranial bleeding, death, and cardiovascular events. Olesen et al22 reported that patients with AF diagnosed with non–end-stage and endstage chronic kidney disease had an increased risk of stroke or systemic thromboembolism. Although renal dysfunction is not included in the component factors of the CHADS2 score or CHA2DS2-VASc score, it is closely related to their component factors, such as heart failure, hypertension, age, diabetes, and vascular disease. In our assessment, rivaroxaban was favored over warfarin in patients with a CrCl less than 50 mL/min and patients with a CrCl of 50 mL/min or more. Because rivaroxaban is administered with a dose reduction according to the CrCl level in clinical practice (Japan: 15 mg, 10 mg; outside Japan: 20 mg, 15 mg), the NCB of rivaroxaban is expected to be further increased.

Limitations Our study has several limitations. First, no adjustment for multiple testing was conducted in this study because initially it had not been designed to assess the NCB of rivaroxaban. Second, although we used 2 different methods to evaluate the NCB of rivaroxaban, our analyses cannot account for all the clinical variables. The adjusted NCB, which was given a weight of 1.5 for ICH, was conducted with an emphasis on intracranial bleeding, partially because this represented the safety concerns surrounding the rivaroxaban benefit–risk profile. Additionally, we employed the composite end point to clarify the NCB in specific population, such as with CHADS2 score and with renal function. Because, the incidence number of ICH itself was not much in the overall of J-ROCKET AF trial (5 in the rivaroxaban group and 10 in the warfarin group). So, it was insufficient power for evaluating the NCB in specific population by Singer’s method. Third, in this composite end point, major bleeding events were regarded as having clinical significance equivalent to that

of the secondary end points, such as stroke, non-CNS systemic embolism, all-cause death, and myocardial infarction. However, in J-ROCKET AF, most of the major bleeding events were transient or reversible and did not cause permanent disability; therefore, the events in this composite end point were not of approximately equal clinical impact or weight. In fact, as far as we know, there are no methods available to estimate the NCB perfectly. Therefore, it is necessary to understand exactly what each method for calculating the NCB signifies.

Conclusion The results of the subanalysis of the J-ROCKET AF trial showed a favorable trend of the NCB of rivaroxaban compared with warfarin. These results show that rivaroxaban could become a new standard of treatment for Japanese patients with AF.

References 1. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983-988. 2. European Heart Rhythm Association, European Association for Cardio-Thoracic SurgeryCamm AJ, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31:2369-2429. 3. Kubitza D, Becka M, Roth A, et al. Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin 2008;24:2757-2765. 4. Kubitza D, Becka M, Wensing G, et al. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939–an oral, direct Factor Xa inhibitor—after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 2005;61:873-880. 5. Perzborn E, Strassburger J, Wilmen A, et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939—an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005;3:514-521. 6. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864-2870. 7. Lip GY, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro heart survey on atrial fibrillation. Chest 2010;137:263-272. 8. Hori M, Matsumoto M, Tanahashi N, et al. Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation—the J-ROCKET AF study. Circ J 2012;76:2104-2111. 9. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719-2747. 10. Skanes AC, Healey JS, Cairns JA, et al. Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke

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prevention and rate/rhythm control. Canad J Cardiol 2012;28:125-136. Pisters R, Lane DA, Nieuwlaat R, et al. A novel userfriendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010;138:1093-1100. Garcia DA. Benefits and risks of oral anticoagulation for stroke prevention in nonvalvular atrial fibrillation. Thromb Res 2012;129:9-16. Singer DE, Chang Y, Fang MC, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Int Med 2009;151:297-305. Friberg L, Rosenqvist M, Lip GY. Net clinical benefit of warfarin in patients with atrial fibrillation: a report from the Swedish atrial fibrillation cohort study. Circulation 2012;125:2298-2307. Japanese guidelines for the management of stroke 2009. J Stroke Cerebrovasc Dis 2011;20:S197-S209. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Eng J Med 2011;365:883-891.

1147 17. Tanigawa T, Kaneko M, Hashizume K, et al. Model-based dose selection for phase III rivaroxaban study in Japanese patients with non-valvular atrial fibrillation. Drug metabol Pharm 2013;28:59-70. 18. Glasziou PP, Irwig LM. An evidence based approach to individualising treatment. BMJ 1995;311:1356-1359. 19. Fang MC, Go AS, Chang Y, et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med 2007;120:700-705. 20. Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003;349:1019-1026. 21. Banerjee A, Lane DA, Torp-Pedersen C, et al. Net clinical benefit of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus no treatment in a ‘real world’ atrial fibrillation population: a modelling analysis based on a nationwide cohort study. Thromb Haemost 2012; 107:584-589. 22. Olesen JB, Lip GY, Kamper AL, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med 2012;367:625-635.

Net clinical benefit of rivaroxaban versus warfarin in Japanese patients with nonvalvular atrial fibrillation: a subgroup analysis of J-ROCKET AF.

The risk factors that have been identified for bleeding events with rivaroxaban are predominantly the same as those predicting thromboembolic ones in ...
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