strokeaha.113.002968.full

1In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial, the efficacy and safety of rivaroxaban, a novel, oral, direct factor Xa inhibitor, was assessed for the prevention of stroke in patients with atrial fibrillation (AF) and at moderate to high risk of stroke.1 Results from this study showed that rivaroxaban

(20 mg once daily or 15 mg once daily in patients with a cre-atinine clearance [CrCl] of 3049 mL/min) was noninferior to dose-adjusted warfarin for the prevention of stroke and sys-temic embolism in an intention-to-treat (ITT) analysis. Rates of major or nonmajor clinically relevant bleeding were not sig-nificantly different between the 2 study groups; however, intra-cranial hemorrhage and fatal bleeding occurred significantly

Background and PurposeIn Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial, rivaroxaban was noninferior to dose-adjusted warfarin in preventing stroke or systemic embolism among patients with nonvalvular atrial fibrillation at moderate to high stroke risk. Because of differences in patient demographics, epidemiology, and stroke risk management in East Asia, outcomes and relative effects of rivaroxaban versus warfarin were assessed to determine consistency among East Asians versus other ROCKET AF participants.

MethodsBaseline demographics and interaction of treatment effects of rivaroxaban and warfarin among patients within East Asia and outside were assessed.

ResultsA total of 932 (6.5%) ROCKET AF participants resided in East Asia. At baseline, East Asians had lower weight, creatinine clearance, and prior vitamin K antagonist use; higher prevalence of prior stroke; and less congestive heart failure and prior myocardial infarction than other participants. Despite higher absolute event rates for efficacy and safety outcomes in East Asians, the relative efficacy of rivaroxaban (20 mg once daily; 15 mg once daily for creatinine clearance of 3049 mL/min) versus warfarin with respect to the primary efficacy end point (stroke/systemic embolism) was consistent among East Asians and nonEast Asians (interaction P=0.666). Relative event rates for the major or nonmajor clinically relevant bleeding in patients treated with rivaroxaban and warfarin were consistent among East Asians and nonEast Asians (interaction P=0.867).

ConclusionsObserved relative efficacy and safety of rivaroxaban versus warfarin were similar among patients within and outside East Asia. Rivaroxaban, 20 mg once daily, is an alternative to warfarin for stroke prevention in East Asians with nonvalvular atrial fibrillation.

Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00123456. (Stroke. 2014;45:00-00.)

Key Words: atrial fibrillation Far East rivaroxaban stroke

Rivaroxaban for Stroke Prevention in East Asian Patients From the ROCKET AF Trial

Ka Sing Lawrence Wong, MD; Dai Yi Hu, MD; Abraham Oomman, MD; Ru-San Tan, MD; Manesh R. Patel, MD; Daniel E. Singer, MD; Gnter Breithardt, MD;

Kenneth W. Mahaffey, MD; Richard C. Becker, MD; Robert Califf, MD; Keith A.A. Fox, MD; Scott D. Berkowitz, MD; Werner Hacke, MD; Graeme J. Hankey, MD;

on behalf of The Executive Steering Committee and the ROCKET AF Study Investigators

Received July 25, 2013; final revision received February 8, 2014; accepted February 27, 2014.From the Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China (K.S.L.W.); Heart

Center, Peking University Peoples Hospital, Beijing, China (D.Y.H.); Department of Cardiology, Apollo Hospital, Chennai, India (A.O.); National Heart Centre, Singapore, Singapore (R.-S.T.); Department of Medicine, Division of Cardiology, Duke Clinical Research Institute (M.R.P., K.W.M., R.C.B.) and Department of Medicine, Division of Cardiology, Duke Translational Medicine Institute (R.C.), Duke University Medical Center, Durham, NC; Department of Epidemiology, Massachusetts General Hospital and Harvard Medical School, Boston (D.E.S.); Department of Cardiovascular Medicine, University Hospital Mnster, Mnster, Germany (G.B.); Centre for Cardiovascular Science, University of Edinburgh and Royal Infirmary of Edinburgh, Edinburgh, Scotland (K.A.A.F.); Bayer HealthCare Pharmaceuticals, Montville, NJ (S.D.B.); Department of Neurology, Ruprecht-Karls-University, Heidelberg, Germany (W.H.); and Stroke Unit, Department of Neurology, Royal Perth Hospital, University of Western Australia, Perth, Australia (G.J.H.).

Guest Editor for this article was Kazunori Toyoda, MD.The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.

113.002968/-/DC1.Correspondence to Ka Sing Lawrence Wong, MD, Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales

Hospital, Hong Kong, China. E-mail [email protected] 2014 American Heart Association, Inc.Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.113.002968

Original Contribution

2 Stroke June 2014

less frequently in the rivaroxaban treatment group. There was no significant interaction in terms of the efficacy and safety of rivaroxaban versus warfarin with respect to race or region.1

Demographic differences exist between Asian populations and other ethnic groups, which may affect the optimal dosing of novel anticoagulants, including rivaroxaban. For example, body weight and body mass index (BMI) values have been shown to be lower in Chinese versus white populations.2 The proportion of strokes that are hemorrhagic has also been shown to be higher in Asians than in whites.3,4 Conversely, there is evi-dence to suggest that cardioembolic strokes make up a greater proportion of strokes in white versus Asian populations.5 Data from 2 studies have also shown East Asian populations to be more sensitive to warfarin than Indian and white populations.6,7 Warfarin may also interact with several food and herbal supple-ments commonly used in Asia, thereby complicating its use.8

There is a perception, and some supporting evidence, that the incidence of intracranial hemorrhage is increased in patients of Asian ethnicity (largely East Asian) who receive warfarin compared with other ethnic groups.9,10 As a result, anticoagulants are underprescribed11,12 or underdosed13 in patients within this region because of the fear that the risk of bleeding offsets any benefits.

As a result of the differences in patient demographics, epidemiology, and stroke risk management in East Asia, out-comes and the relative effects of rivaroxaban versus warfarin were assessed as to whether they were consistent among East Asians and nonEast Asians who participated in ROCKET AF, particularly because warfarin was targeted to an interna-tional normalized ratio (INR) range of 2.0 to 3.0.

MethodsOverview of the ROCKET AF StudyThe ROCKET AF was a randomized, multicenter, double-blind, double-dummy, event-driven study that was performed at 1178 participating sites in 45 countries.1 The trial was supported by Janssen Research and Development, LLC, and Bayer HealthCare Pharmaceuticals. The Duke Clinical Research Institute coordinated the trial, managed the database, and performed all primary analyses independently of the sponsors; the trial itself was conducted by a global consortium.14 The protocol was approved by pertinent national regulatory authorities and ethics committees at participating centers.

The objective of ROCKET AF was to compare once-daily rivaroxa-ban with dose-adjusted warfarin for the prevention of stroke and systemic embolism in patients with nonvalvular AF and at moderate to high risk of stroke. Patients enrolled in ROCKET AF were randomly assigned to fixed-dose rivaroxaban (20 mg once daily or 15 mg once daily in patients with a CrCl of 3049 mL/min) or adjusted-dose warfarin (target INR, 2.03.0). To maintain blinding, patients within each group were also given a matching placebo. The primary efficacy end point was the composite of stroke (ischemic or hemorrhagic) and noncentral nervous system (CNS) systemic embolism. The principal safety outcome was the composite of major and nonmajor clinically relevant bleeding. Major bleeding was de-fined as clinically overt bleeding associated with any of the following: fatal bleeding, critical organ bleeding, hemoglobin drop 2 g/dL, or trans-fusions of 2 U of whole blood or packed red blood cells.

Analysis of the East Asian Cohort of ROCKET AFA secondary analysis of results from randomized patients from 73 sites in 4 geographic areas in East Asia (China, Korea, Taiwan, and Hong Kong) who participated in the full ROCKET AF study was performed. Efficacy and safety results for patients of different ethnicities within

a given geographic region are not available (eg, patients of Asian or white ethnicity resident in East Asia). Therefore, for the purposes of this secondary analysis, it was assumed that residence in East Asia is a surrogate for ethnicity. Patients enrolled in ROCKET AF in the East Asian region were randomized to the same study regimen as patients in other regions. The same efficacy end points and safety outcomes as defined in ROCKET AF (composite of stroke or systemic embolism, major and nonmajor clinically relevant bleeding, etc) in patients from the East Asian region were compared with patients from the remaining ROCKET AF population (ie, excluding those at the 73 sites in the 4 geographic areas). These 4 areas were considered to be most represen-tative of the East Asian region as a whole, although it should be noted that no patients from Japan were enrolled in ROCKET AF. A separate trial of rivaroxaban versus warfarin in patients with nonvalvular AF, known as J-ROCKET AF, was conducted in Japan, in which a lower 15 mg once-daily dose was given based on pharmacokinetic modeling and in line with specific Japanese clinical practice patterns and guide-line recommendations for reduced target INR levels.15,16

Patient Baseline DemographicsBaseline demographics were assessed for patients in the East Asian region and remaining ROCKET AF population. Demographics analyzed included age, weight, BMI, and CrCl; prior vitamin K antagonist (VKA) and acetylsalicylic acid (ASA) use; baseline congestive heart failure, diabetes mellitus, and hypertension; and prior stroke, transient ischemic attack (TIA), non-CNS systemic embolism, and myocardial infarction.

Statistical AnalysesThe ITT population included all patients who were randomized in the study, whereas the safety population included all patients who received 1 dose of a study drug. On treatment was defined as the period from the date of the first double-blind study medication to the date of the last double-blind study medication administration plus 2 days. Site notification was defined as notification to the sites when the required number of primary efficacy end point events had been reached. In the current subanalysis, estimates and 2-sided 95% con-fidence intervals (CIs) for the hazard ratio (HR; rivaroxaban versus warfarin) for patients residing within and outside East Asia are shown in the ITT population until site notification for all efficacy end points and in the safety population while on treatment for all safety out-comes. HRs for patients residing within versus outside East Asia, ir-respective of treatment assignment, have also been estimated for the primary efficacy end point and for the principal safety outcome.

Cox proportional hazards regression models were used with treat-ment, residence status (within or outside the East Asian region), and the treatment by residence status interaction as covariates to test for interaction between the differential effects of rivaroxaban and warfarin on stroke or non-CNS systemic embolism (primary efficacy end point) and major or nonmajor clinically relevant bleeding (principal safety outcome) among patients residing within and outside East Asia. The interaction of treatment group by residence status for predefined sec-ondary efficacy end points and safety outcomes was also assessed. For selected significant interactions, HRs for patients residing within ver-sus outside East Asia were also assessed within each treatment group. It should be noted that any significant P values should be considered nominal only because of the large number of comparisons that have been performed on the database. There is also limited power to detect significant differences because of the small East Asian sample size.

The linear interpolation method of Rosendaal et al17 was used to calculate the overall time that INR values fell within the therapeutic range of 2.0 to 3.0 for the warfarin group. A comparative analysis of treatment efficacy according to quartiles of time that INR values fell within the therapeutic range at participating study centers in the East Asian region was also performed. For both East Asian and nonEast Asian patient groups, center time in therapeutic range (cTTR) was calculated using the total number of INR values in target range from all subjects on warfarin within a center divided by the total number of INR values from all subjects on warfarin within the same center. Centers were categorized into quartiles with approximately equal

Wong et al Rivaroxaban for Stroke Prevention 3

numbers of subjects in each. Analyses of cTTR were calculated for the safety population while on treatment.

ResultsPatient RecruitmentA total of 932 patients (China [n=496], Korea [n=204], Taiwan [n=159], Hong Kong [n=73]) formed the ITT population in the ROCKET AF East Asian cohort. This equates to 6.5% of the 14 264 patients randomized in the full ROCKET AF study. In total, 928 ITT patients from the ROCKET AF East Asian cohort received 1 dose of study drug and therefore formed the safety

population. The patient disposition for the ROCKET AF East Asian cohort is summarized in Figure I in the online-only Data Supplement. The median duration of treatment exposure in the East Asian subanalysis was 553 days, whereas the median fol-low-up period was 668 days. This compares with 593 and 708 days, respectively, in the remaining study population.

Patient Baseline DemographicsBaseline demographics by treatment arm for patients in the East Asian cohort of ROCKET AF and the ROCKET AF popula-tion excluding East Asia are shown in Table 1. Baseline patient

Table 1. Baseline Characteristics of the Intention-to-Treat Population in the ROCKET AF East Asian Cohort and the Remaining Study Population

East Asian Cohort (N=932) ROCKET AF Excluding East Asia (N=13 322)

Rivaroxaban (n=468) Warfarin (n=464) Rivaroxaban (n=6663) Warfarin (n=6669)

Mean age, y 69.6 69.7 71.3 71.3

Mean baseline weight, kg 67.3 66.4 83.1 82.7

Median BMI, kg/m2 25.0 24.8 28.6 28.4

Baseline mean creatinine clearance, mL/min 64.0 66.1 73.6 73.0

Prior vitamin K antagonist use, % 48.5 49.6 63.3 63.4

Prior chronic ASA use, % 37.0 39.4 36.2 36.5

Baseline congestive heart failure, % 38.9 38.4 64.3 63.9

Baseline diabetes mellitus, % 38.3 35.6 40.5 39.8

Baseline hypertension, % 79.3 80.6 91.0 91.5

Prior stroke/TIA/non-CNS systemic embolism, % 65.0 65.1 54.2 53.9

Prior myocardial infarction 3.6 7.3 17.5 18.8

Mean baseline CHADS2 score 3.2 3.2 3.5 3.5

CHA2DS

2-VASc, %

1 0.0 0.0 0.0

4 Stroke June 2014

characteristics were similar between the 2 treatment arms in the East Asian cohort. Compared with patients residing outside the East Asian region, patients in the East Asian cohort were younger and had a lower body weight and BMI, and fewer patients had congestive heart failure, hypertension, or previous myocardial infarction at baseline. Mean baseline CrCl was also lower for patients in the ROCKET AF East Asian cohort versus patients outside this region. Conversely, levels of prior stroke/TIA/non-CNS systemic embolism, as well as the percentage of VKA-naive patients, were higher in the ROCKET AF East Asian cohort than in the remaining study population.

Mean baseline congestive heart failure, hypertension, age, diabetes, prior stroke/TIA (CHADS2) scores were lower for patients in the East Asian cohort (3.2 in both the rivaroxa-ban and warfarin treatment arms) than for patients outside East Asia (3.5 in both treatment arms). A greater number of East Asian patients in ROCKET AF had a baseline CHADS2 score of 2 (rivaroxaban, 24.2%; warfarin, 23.9%) compared with the nonEast Asian population (rivaroxaban, 12.2%;

warfarin, 12.3%). This is consistent with the observation of higher prevalence of prior stroke or TIA observed among East Asian patients, which would confer a CHADS2 score of 2 in the absence of other risk factors. Conversely, fewer East Asian patients in ROCKET AF had a score 4 (rivaroxaban, 35.7%; warfarin, 31.9%) compared with the rest of the study popula-tion (rivaroxaban, 44.7%; warfarin, 43.3%).

Efficacy End PointsIn the East Asian cohort, the observed annual event rates for the primary efficacy end point of stroke or systemic embo-lism were numerically higher (2.6% and 3.4% per year in the rivaroxaban and warfarin arms, respectively [HR=0.78; 95% CI, 0.441.39]) compared with corresponding annual rates in the remaining ROCKET AF population (2.1% and 2.4% per year [HR=0.89; 95% CI, 0.751.05]). However, no significant interaction between treatment and residen-tial status was identified (P=0.666; Figure 1 and Table 2). The efficacy of rivaroxaban versus warfarin for the primary

Figure 1. Intention-to-treat analyses of efficacy end point events. This is a post hoc analysis that has not been corrected for multiple analyses. CNS indicates central nervous system; MRS, modified Rankin scale score; and ROCKET AF, Rivaroxaban Once Daily Oral Direct Fac-tor Xa Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation. *Haz-ard ratio (95% confidence interval [CI]) from the Cox proportional hazard model with treatment as a covariate. P value for the interaction of treatment group and residence location (East Asia vs nonEast Asia) for the indicated outcome. Statisti-cally significant at nominal 0.05 (2-sided).


efficacy end point was therefore consistent among patients residing within and outside East Asia. The observed efficacy of rivaroxaban versus warfarin for the primary efficacy end point was also consistent across all prespecified subgroups in the ROCKET AF East Asian cohort, including patients with mild or moderate renal impairment (Figure II in the online-only Data Supplement).

Observed rates of the 2 prespecified composite second-ary efficacy end points (stroke, non-CNS systemic embo-lism, and vascular death; and stroke, non-CNS systemic embolism, myocardial infarction, and vascular death) were numerically lower in the rivaroxaban treatment group than in the warfarin treatment group of the East Asian cohort (Figure 1). The observed rate of all-cause stroke was also lower in the rivaroxaban treatment group. Overall, 4 East Asian patients (0.5% per year) in the rivaroxaban arm had a hemorrhagic stroke compared with 10 patients (1.2% per year) in the warfarin arm (HR=0.40; 95% CI, 0.131.27). Observed rates of all-cause mortality were also nonsignif-icantly lower with rivaroxaban (2.6% per year) than with warfarin (3.6% per year [HR=0.73; 95% CI, 0.411.27]), although rates of myocardial infarction were the same in both treatment arms (1.0% per year in each treatment arm [HR=1.00; 95% CI, 0.382.66]).

When studying the 2 geographical areas, there was a strong trend toward increased rates of stroke or systemic embolism

in the East Asian cohort versus the remaining study popu-lation irrespective of treatment assignment (HR=1.34; 95% CI, 1.001.80; P=0.053; Table 2). Observed annual rates of all-cause stroke, hemorrhagic stroke, ischemic stroke, non-disabling stroke, and disabling stroke were all higher in the ROCKET AF East Asian cohort than in the remaining study population (Figure 1). These differences may be more marked if adjusted for the lower baseline CHADS2 score in East Asian patients. However, there was no significant inter-action between treatment and residential status, indicating that the relative efficacy of rivaroxaban versus warfarin for these stroke outcomes was consistent between the 2 study populations. There was also no significant interaction identi-fied for the other secondary efficacy end points (non-CNS systemic embolism; myocardial infarction; all-cause, vascu-lar, and nonvascular death; Figure 1).

INR and cTTR AnalysesAmong warfarin-treated patients in the ROCKET AF East Asian cohort, patient INR values were within the therapeu-tic range (2.03.0) for a mean of 47.1% of the time versus 55.7% for the ROCKET AF population excluding East Asia. INR values were between 1.5 and

6 Stroke June 2014

With regard to cTTR, no interaction with treatment effect was apparent when assessing rivaroxaban for the primary effi-cacy end point in the East Asian cohort (P=0.585 for interac-tion; Table 3).

Safety OutcomesIn the ROCKET AF East Asian cohort, the annual event rates for major or nonmajor clinically relevant bleeding (the prin-cipal safety outcome) were 20.9% and 20.7% per year in the rivaroxaban and warfarin arms, respectively (HR=1.01; 95%

CI, 0.791.30; Table 4). This compares with 14.5% and 14.1%, respectively, per year in the ROCKET AF population exclud-ing East Asia (HR=1.03; 95% CI, 0.961.11). However, no sig-nificant interaction between treatment and residence status was identified (P=0.867; Figure 2 and Table 4). With the exception of patients with prior ASA use (patients who had not received prior ASA and who were prescribed rivaroxaban had a lower rate of the principal safety outcome; conversely, patients who had received prior ASA and who were prescribed warfarin had a lower rate of the principal safety outcome), there were no

Table 4. Principal Safety Outcome of Major or Nonmajor Clinically Relevant Bleeding in the Safety Population During Treatment

Cohort

Rivaroxaban Warfarin Rivaroxaban vs Warfarin East Asia vs NonEast Asia*

Hazard Ratio (95% CI)n/NEvent Rate, %

per Year n/NEvent Rate, %

per Year Hazard Ratio (95% CI) Interaction P Value

ROCKET AF East Asian cohort

121/466 20.9 122/462 20.7 1.01 (0.791.30) 0.867 1.42 (1.251.62); P


significant interactions between treatment group and any pre-specified subgroup in the ROCKET AF East Asian cohort for the principal safety outcome, including patients with mild or moderate renal impairment (Figures III and IV in the online-only Data Supplement).

Rivaroxaban was also associated with reductions in critical organ bleeding and intracranial hemorrhage relative to warfa-rin in the East Asian cohort. Overall, there were 5 (0.7% per year) and 18 (2.6% per year) critical organ bleeding events in the rivaroxaban and warfarin treatment arms, respectively (HR=0.28; 95% CI, 0.100.75). Rates of intracranial hemor-rhage with rivaroxaban versus warfarin were 4 (0.6% per year) and 17 (2.5% per year) events, respectively, in each treatment group (HR=0.24; 95% CI, 0.080.71). Furthermore, there was a significant interaction between treatment and residence within or outside East Asia for intracranial hemorrhage in ROCKET AF (interaction P=0.044; Figure 2). Among patients receiv-ing rivaroxaban, there was no significant difference in the rate of intracranial hemorrhage for East Asians versus nonEast Asians (HR=1.20; 95% CI, 0.433.31; P=0.73; Table I in the online-only Data Supplement). Conversely, among patients receiving warfarin, the rate of intracranial hemorrhage was significantly greater in East Asian patients than in nonEast Asian patients (HR=3.89; 95% CI, 2.296.63; P

8 Stroke June 2014

versus warfarin is an important finding given the concern over the higher rates of hemorrhagic stroke and intracranial hemor-rhage in Asian populations. Although statistical significance was not attained for the East Asian results, the results are con-sistent with the nominally significant results for patients out-side East Asia and with the results of the overall trial.1

There are several possible reasons why the uptake of VKAs is relatively low in East Asia, one in particular being the fear of intracranial hemorrhage. Rates of intracranial hemorrhage have been shown to be higher in Asians than in other ethnic groups receiving warfarin.9,10 As a result of the concern around bleeding risk in East Asia, patients in this region are underprescribed11,12 or underdosed13 anticoagulants. Although there is limited evidence to support a lower INR range for warfarin in East Asian patients, a study in Chinese patients receiving warfarin therapy suggested that a target range of 1.8 to 2.4 may be preferable.22 The Chinese Current Knowledge and Management Recommendations in AF 2010 guidelines recommend that warfarin should be adminis-tered on a long-term basis at a target INR of 1.6 to 2.5 in patients with nonmechanical valvular AF with high and intermediate risk factors for stroke.13 However, Taiwanese and Korean stroke guidelines recommend an INR target of 2.0 to 3.0 when admin-istering warfarin to patients with AF who are at risk of stroke.23,24 These latter guidelines are in line with internationally used AF guidelines such as those produced by the European Society of Cardiology and the American College of Chest Physicians.25,26 In this secondary analysis, there was a significant increase in intra-cranial hemorrhage in East Asian patients receiving warfarin ver-sus nonEast Asian patients. In contrast, there was no significant difference in the rate of intracranial hemorrhage in East Asian versus nonEast Asian patients receiving rivaroxaban, and this has important safety implications for the use of rivaroxaban in this region. One possible reason for the increased risk of intra-cranial hemorrhage in East Asian patients receiving warfarin could be the greater number of patients in this group who were VKA naive compared with the remaining study populationthe risk of major hemorrhage is known to be higher in VKA-naive patients when they first start taking VKAs.27 In addition, warfa-rin has been shown to interact with some herbal products that are commonly used in the Asia-Pacific region. The risk of bleed-ing is increased when warfarin is combined with some of these products, including ginkgo and garlic.8 However, it is unknown whether this was a contributory factor in this secondary analysis. As well as the increased risk of intracranial hemorrhage in East Asian patients receiving warfarin, the reduction in intracranial hemorrhage with rivaroxaban compared with warfarin in this cohort is also a significant finding, especially considering the rel-atively low number of patients (n=932) included in this analysis.

As well as the reduction in intracranial hemorrhage, rates of critical organ bleeding were also lower with rivaroxaban in the ROCKET AF East Asian cohort. It should be noted that there was no apparent increase in major bleeding events for rivaroxaban versus warfarin because of hemoglobin drops or transfusions in the ROCKET AF East Asian cohort, in contrast to the ROCKET AF population outside this region. Observed rates of fatal bleeding were also lower with rivaroxaban ver-sus warfarin in the East Asian patient population. These are important findings because patients in the Asian region are prone to have more bleeding events (Table 4).9,10

Broadly comparable results were observed in a recent analysis of Asian patients with AF enrolled in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial of dabiga-tran versus warfarin,28 in that Asian patients experienced somewhat greater rates of stroke or systemic embolism than non-Asians, irrespective of treatment group. However, in contrast to this study, rates of intracranial hemorrhage in Asian patients receiving warfa-rin were only slightly greater than in non-Asian patients and there was no significant interaction between ethnic group (Asian versus non-Asian) and the treatment effect of dabigatran versus warfarin. In the recently published Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation (ENGAGE AF) study, the data from patients in the Asia region were consistent with the overall trial results, that is, edoxaban was noninferior to warfarin with respect to the prevention of stroke or systemic embolism and was associated with significantly lower rates of bleeding.29

Study LimitationsWhen analyzing the results from this secondary analysis, it should be noted that the number of patients in the East Asian cohort was relatively low, which limits the power of the vari-ous outcomes and can make extrapolation of the results dif-ficult. Other limitations of this analysis are that it involved a subgroup from the main ROCKET AF study and that not all countries in the East Asian region were represented. Although it was assumed that residence in East Asia was a surrogate for ethnicity for the purposes of this analysis, data generated are for the population of the geographic area as a whole.

ConclusionsSeveral demographic and epidemiological differences exist for the ROCKET AF East Asian cohort compared with participants in ROCKET AF outside this region. Despite these differences, efficacy and safety results were broadly consistent for patients in ROCKET AF who resided within and outside the East Asian region. Furthermore, intracranial hemorrhage and critical organ bleeding were considerably reduced with rivaroxaban com-pared with warfarin in the East Asian cohort. Thus, this analysis supports the use of rivaroxaban at 20 mg once daily (15 mg once daily for CrCl of 3049 mL/min) for the prevention of stroke and systemic embolism as an alternative to warfarin in adult patients with nonvalvular AF in the East Asian region.

AcknowledgmentsWe thank Michael Barton who provided medical writing services with funding from Janssen Scientific Affairs, LLC, and Bayer HealthCare Pharmaceuticals.

Sources of FundingThe ROCKET study was funded by Janssen Research and Development, LLC, and Bayer HealthCare Pharmaceuticals.

DisclosuresDr Wong has received honoraria as a member of a steering commit-tee for Johnson & Johnson and Bayer; and also for participation in clinical trials, contributions to advisory boards, or oral presentations from Bayer, Sanofi-Aventis, Bristol-Myers Squibb, Boehringer Ingelheim, and Pfizer. Dr Oomman has received honoraria from Bayer HealthCare. Dr Tan has received consultancy, advisory board,


and lecture fees from Bayer HealthCare and Pfizer; and consultancy and advisory board fees from Boehringer Ingelheim, Bristol-Myers Squibb, Johnson & Johnson, AstraZeneca, and Servier. Dr Patel has received research grant from AstraZeneca and consulting fees from Ortho-McNeil-Janssen and Bayer HealthCare and serves on the ad-visory board for Genzyme. Dr Singer has served as consultant to Bayer HealthCare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Pfizer, and CSL Behring; has received research support from Johnson & Johnson; and owns no shares in any company that would pose a conflict of interest. Dr Breithardt has received honoraria from Johnson & Johnson and Bayer; and advisory board fees from Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and Sanofi-Aventis. Dr Mahaffey has received grant support (significant) from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Merck, Portola, Regado Biotechnologies, Sanofi, Schering-Plough (now Merck), and The Medicines Company; significant consulting fees from Bayer, Johnson & Johnson; and modest consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Merck, Ortho/McNeill, Pfizer, Polymedix, and Sanofi; all full disclosure can be found at www.dcri.org. Dr Becker has received modest research support from Bayer and Johnson & Johnson and serves on the scientific advisory boards for Bayer. Dr Califf has received con-sulting fees and other service from Bayer, Bristol-Myers Squibb Foundation, CV Sight, LLC, DSI-Lilly, Gambro, Heart.org, Janssen R&D, LLC, Kowa, Novartis; all other industry interactions are list-ed at www.dcri.org. Dr Fox has received grant support and lecture fees from Bayer, Janssen, Eli Lilly, AstraZeneca; and lecture fees from Sanofi-Aventis. Dr Berkowitz has been employed as a clinical research physician at Bayer HealthCare Pharmaceuticals; holds no other consultancies, board memberships, stock, or stock options; and does not receive grants, royalties, consulting fees or honoraria, payment for lectures, or payment for manuscript preparation. Dr Hacke has received honoraria for serving on an executive com-mittee for Johnson & Johnson and Bayer and advisory board fees from Boehringer Ingelheim. Dr Hankey has received consultancy fees from advisory boards for Bayer Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, and Pfizer; has received hono-raria for speaking at scientific symposia sponsored by Bayer Pharmaceuticals and web-based education programs of heart.org; is a member of the ROCKET AF Executive Steering Committee; and has no shareholdings or funding grants. Dr Hu reports no conflicts.

References 1. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al;

ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883891.

2. Wang D, Li Y, Lee SG, Wang L, Fan J, Zhang G, et al. Ethnic differences in body composition and obesity related risk factors: study in Chinese and white males living in China. PLoS One. 2011;6:e19835.

3. Thrift AG, Dewey HM, Macdonell RA, McNeil JJ, Donnan GA. Incidence of the major stroke subtypes: initial findings from the North East Melbourne stroke incidence study (NEMESIS). Stroke. 2001;32:17321738.

4. Zhang LF, Yang J, Hong Z, Yuan GG, Zhou BF, Zhao LC, et al; Collaborative Group of China Multicenter Study of Cardiovascular Epidemiology. Proportion of different subtypes of stroke in China. Stroke. 2003;34:20912096.

5. Ng WK, Goh KJ, George J, Tan CT, Biard A, Donnan GA. A compara-tive study of stroke subtypes between Asians and Caucasians in two hospital-based stroke registries. Neurol J Southeast Asia. 1998;3:1926.

6. Zhao F, Loke C, Rankin SC, Guo JY, Lee HS, Wu TS, et al. Novel CYP2C9 genetic variants in Asian subjects and their influence on main-tenance warfarin dose. Clin Pharmacol Ther. 2004;76:210219.

7. Yuen E, Gueorguieva I, Wise S, Soon D, Aarons L. Ethnic differences in the population pharmacokinetics and pharmacodynamics of warfarin. J Pharmacokinet Pharmacodyn. 2010;37:324.

8. Fugh-Berman A. Herb-drug interactions. Lancet. 2000;355:134138.

9. Shen AY, Yao JF, Brar SS, Jorgensen MB, Chen W. Racial/ethnic differ-ences in the risk of intracranial hemorrhage among patients with atrial fibrillation. J Am Coll Cardiol. 2007;50:309315.

10. Shen AY, Chen W, Yao JF, Brar SS, Wang X, Go AS. Effect of race/eth-nicity on the efficacy of warfarin: potential implications for prevention of stroke in patients with atrial fibrillation. CNS Drugs. 2008;22:815825.

11. Wen-Hang QI; Society of Cardiology, Chinese Medical Association. Retrospective investigation of hospitalised patients with atrial fibrillation in mainland China. Int J Cardiol. 2005;105:283287.

12. Gao Q, Fu X, Wei JW, Chen X, Huang Y, Wang J, et al; China QUEST Study Investigators. Use of oral anticoagulation among stroke patients with atrial fibrillation in China: the ChinaQUEST (Quality evaluation of stroke care and treatment) registry study. Int J Stroke. 2013;8:150154.

13. Huang CX, Zhang S, Ma CS, Yang YZ, Huang DJ, Cao KJ, et al. Current knowledge and management recommendations of atrial fibrillation. Chin J Cardiac Arrhythmia. 2010;14:328369.

14. ROCKET AF Study Investigators. Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study. Am Heart J. 2010;159:340347.e1.

15. Atarashi H, Inoue H, Okumura K, Yamashita T, Kumagai N, Origasa H; J-RHYTHM Registry Investigators. Present status of anticoagulation treatment in Japanese patients with atrial fibrillation: a report from the J-RHYTHM Registry. Circ J. 2011;75:13281333.

16. Hori M, Matsumoto M, Tanahashi N, Momomura S, Uchiyama S, Goto S, et al. Rivaroxaban vs. warfarin in Japanese patients with atrial fibrilla-tion the J-ROCKET AF study. Circ J. 2012;76:21042111.

17. Rosendaal FR, Cannegieter SC, van der Meer FJ, Brit E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost. 1993;69:236239.

18. Mueck W, Eriksson BI, Bauer KA, Borris L, Dahl OE, Fisher WD, et al. Population pharmacokinetics and pharmacodynamics of rivaroxabanan oral, direct factor Xa inhibitorin patients undergoing major orthopaedic surgery. Clin Pharmacokinet. 2008;47:203216.

19. Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Body weight has lim-ited influence on the safety, tolerability, pharmacokinetics, or pharma-codynamics of rivaroxaban (BAY 59-7939) in healthy subjects. J Clin Pharmacol. 2007;47:218226.

20. Kim AS, Johnston SC. Global variation in the relative burden of stroke and ischemic heart disease. Circulation. 2011;124:314323.

21. Hankey GJ, Patel MR, Stevens SR, Becker RC, Breithardt G, Carolei A, et al; ROCKET AF Steering Committee Investigators. Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. Lancet Neurol. 2012;11:315322.

22. You JH, Chan FW, Wong RS, Cheng G. Is INR between 2.0 and 3.0 the opti-mal level for Chinese patients on warfarin therapy for moderate-intensity anticoagulation? Br J Clin Pharmacol. 2005;59:582587.

23. Chang YJ, Ryu SJ, Chen JR, Hu HH, Yip PK, Chiu TF; Consensus Group of Taiwan Stroke Society. [Guidelines for the general management of patients with acute ischemic stroke]. Acta Neurol Taiwan. 2008;17:275294.

24. Korean Clinical Research Center for Stroke. Clinical Practice Guidelines for Stroke. 2010. http://www.stroke-crc.or.kr/cpgs%20for%20stroke%20(english).pdf. Accessed January 1, 2011.

25. Camm AJ, Kirchhof P, Lip GYH, Schotten U, Savelieva I, Ernst S, 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;31:23692429.

26. You JJ, Singer DE, Howard PA, Lane DA, Eckman MH, Fang MC, et al; American College of Chest Physicians. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e531Se575S.

27. Garcia DA, Lopes RD, Hylek EM. New-onset atrial fibrillation and war-farin initiation: high risk periods and implications for new antithrom-botic drugs. Thromb Haemost. 2010;104:10991105.

28. Hori M, Connolly SJ, Zhu J, Liu LS, Lau CP, Pais P, et al; RE-LY Investigators. Dabigatran versus warfarin: effects on ischemic and hem-orrhagic strokes and bleeding in Asians and non-Asians with atrial fibril-lation. Stroke. 2013;44:18911896.

29. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:20932104.

strokeaha.113.002968.full

Documents