1739

See related article, p 1608.

In 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 moder-ate 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 creatinine clearance [CrCl] of 30–49 mL/min) was non-inferior to dose-adjusted warfarin for the prevention of stroke and systemic embolism in an intention-to-treat (ITT) analysis. Rates of major or nonmajor clinically relevant bleeding were

Background and Purpose—In 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.

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

Results—A 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 30–49 mL/min) versus warfarin with respect to the primary efficacy end point (stroke/systemic embolism) was consistent among East Asians and non–East 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 non–East Asians (interaction P=0.867).

Conclusions—Observed 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 Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00123456. (Stroke. 2014;45:1739-1747.)

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; Günter 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 People’s 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 Münster, Münster, 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 ks-wong@cuhk.edu.hk© 2014 American Heart Association, Inc.

Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.113.002968

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1740 Stroke June 2014

not significantly different between the 2 study groups; however, intracranial hemorrhage and fatal bleeding occurred signifi-cantly 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 non–East 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 30–49 mL/min) or adjusted-dose warfarin (target INR, 2.0–3.0). 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 non–central 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 guideline 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 calcu-late 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 ef-ficacy according to quartiles of time that INR values fell within the thera-peutic range at participating study centers in the East Asian region was also performed. For both East Asian and non–East 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

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Wong et al Rivaroxaban for Stroke Prevention 1741

warfarin within the same center. Centers were categorized into quartiles with approximately equal 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

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 <0.1

2 5.6 6.5 2.6 2.5

3 20.1 20.3 11.1 11.9

4 30.1 27.6 25.5 25.1

5 26.5 26.5 30.2 29.8

6 12.4 12.7 19.4 19.1

7 4.3 5.6 8.5 8.4

8 0.9 0.9 2.5 2.8

9 0.2 0.0 0.2 0.4

CHA2DS

2-VASc, mean 4.4 4.4 4.9 4.9

HAS-BLED, %

0 0.9 1.1 0.6 0.6

1 6.2 6.0 7.0 7.0

2 29.9 26.9 30.5 29.6

3 38.7 37.7 41.5 42.2

4 18.8 23.1 18.0 18.0

5 5.1 4.7 2.4 2.6

6 0.4 0.4 0.1 0.1

HAS-BLED, mean 2.9 2.9 2.8 2.8

Time within 1.5–<2.0, % … 29.9 … 20.0

Time within 2.0–3.0, % … 47.1 … 55.7

ASA indicates acetylsalicylic acid; BMI, body mass index; CHADS2, congestive heart failure, hypertension, age, diabetes, prior stroke/TIA; CHA

2DS

2-VASc, CHADS

2,

vascular disease, age, sex category; CNS, central nervous system; HAS-BLED, hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol; ROCKET AF, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; and TIA, transient ischemic attack.

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1742 Stroke June 2014

population excluding East Asia are shown in Table 1. Baseline patient 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 (CHADS

2) scores were lower for

patients in the East Asian cohort (3.2 in both the rivaroxaban 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 CHADS

2 score

of 2 (rivaroxaban, 24.2%; warfarin, 23.9%) compared with

the non–East Asian population (rivaroxaban, 12.2%; warfa-rin, 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 CHADS

2 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, 0.44–1.39]) compared with corresponding annual rates in the remaining ROCKET AF population (2.1% and 2.4% per year [HR=0.89; 95% CI, 0.75–1.05]). However, no signifi-cant interaction between treatment and residential status was identified (P=0.666; Figure 1 and Table 2). The efficacy of

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 non–East Asia) for the indicated outcome. Statisti-cally significant at nominal 0.05 (2-sided).

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Wong et al Rivaroxaban for Stroke Prevention 1743

rivaroxaban versus warfarin for the primary 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, 0.13–1.27). 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, 0.41–1.27]), 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, 0.38–2.66]).

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, 1.00–1.80; 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 CHADS

2 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 (2.0–3.0) 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 <2.0 for a total mean of 29.9% and 20.0% of the time for warfarin-treated patients in the ROCKET AF East Asian cohort and the ROCKET AF population excluding East Asia, respectively (Table 1).

Table 2. Primary Efficacy End Point of Stroke or Systemic Embolism in the Intention-to-Treat Population Until Site Notification*

Analysis Method

Rivaroxaban Warfarin Rivaroxaban vs Warfarin East Asia vs Non–East 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 21/468 2.6 27/464 3.4 0.78 (0.44–1.39) 0.666 1.34 (1.00–1.80);P=0.053ROCKET AF (excluding East Asia) 248/6613 2.1 279/6626 2.4 0.89 (0.75–1.05)

CI indicates confidence interval; and ROCKET AF, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation.

*The median follow-up period was 668 and 708 days for the intention-to-treat population in the ROCKET AF East Asian cohort and remaining ROCKET AF study population, respectively.

†Irrespective of treatment.‡Number of events per 100 patient-years of follow-up.§Hazard ratios (95% CI) from the Cox proportional hazard model with treatment as a covariate.║P value for the interaction of treatment group and each baseline subgroup based on the Cox proportional hazard model including treatment group, baseline

subgroup, and their interaction. Statistically significant at nominal 0.05 (2-sided).

Table 3. Primary Efficacy Treatment Effect by Quartiles of Center Time in Therapeutic Range in the ROCKET AF East Asian Cohort*†

Rivaroxaban Warfarin Rivaroxaban vs WarfarinHR (95% CI)§cTTR,% ‡ n/N (%) Event Rate, % per Year‡ n/N (%) Event Rate, % per Year‡

0.00–41.94 3/114 (2.6) 2.0 3/115 (2.6) 1.7 1.20 (0.24–5.95)

42.19–47.82 2/109 (1.8) 1.2 5/107 (4.7) 3.4 0.36 (0.07–1.87)

49.89−57.92 4/119 (3.4) 2.4 9/113 (8.0) 5.5 0.43 (0.13–1.41)

58.21−73.13 5/112 (4.5) 2.9 6/127 (4.7) 3.0 0.97 (0.29–3.17)

Values presented as number of subjects with events/number of subjects in each cTTR quartile (%). Analysis based on the first event in the safety population during treatment: n=466 for the rivaroxaban arm and n=462 for the warfarin arm. CI indicates confidence interval; cTTR, center time in therapeutic range; HR, hazard ratio; and ROCKET AF, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation.

*P value for interaction=0.585.†International normalized ratio, 2.0–3.0 inclusive.‡Number of events per 100 patient-years of follow-up.§HR (95% CI) from the Cox proportional hazard model with treatment as a covariate.

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1744 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, 0.79–1.30; 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, 0.96–1.11). 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 Non–East 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 (0.79–1.30) 0.867 1.42 (1.25–1.62); P<0.0001

ROCKET AF (excluding East Asia)

1354/6645 14.5 1327/6663 14.1 1.03 (0.96–1.11)

CI indicates confidence interval; and ROCKET AF, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation.

*Irrespective of treatment.†Number of events per 100 patient-years of follow-up. All analyses are based on the time to the first event.‡Hazard ratios (95% CI) from the Cox proportional hazard model with treatment as a covariate.§P value for the interaction of treatment group and each baseline subgroup based on the Cox proportional hazard model including treatment group, baseline subgroup,

and their interaction. Statistically significant at nominal 0.05 (2-sided).

Figure 2. Safety population analyses of safety outcome events. This is a post hoc analysis that has not been corrected for multiple analyses. ROCKET AF indicates 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 non–East Asia) for the indicated outcome. Statisti-cally significant at nominal 0.05 (2-sided). ‡Irrespective of treatment group, the difference between East Asians and non–East Asians with respect to major bleeding was not significant (hazard ratio [HR]=1.23; 95% CI, 0.94–1.60; P=0.14). §Bleeding events were considered to be critical if they occurred in intracra-nial, intraspinal, intraocular, pericardial, intra-articular, intramuscular (with com-partment syndrome), or retroperitoneal sites. ║See Table I in the online-only Data Supplement.

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Wong et al Rivaroxaban for Stroke Prevention 1745

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, 0.10–0.75). 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, 0.08–0.71). 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 non–East Asians (HR=1.20; 95% CI, 0.43–3.31; 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 non–East Asian patients (HR=3.89; 95% CI, 2.29–6.63; P<0.0001; Table I in the online-only Data Supplement).

Among East Asian patients, there were 20 events with hemo-globin drop ≥2 g/dL in each of the rivaroxaban (3.0% per year) and warfarin (2.9% per year) treatment groups. Rivaroxaban was associated with fewer transfusion events than warfarin, with 8 (1.2% per year) and 15 events (2.2% per year), respectively, in each group (HR=0.54; 95% CI, 0.23–1.28). There were also fewer fatal bleeding events observed with rivaroxaban (0.2% per year) than with warfarin (1.0% per year [HR=0.14; 95% CI, 0.02–1.16]).

The risk of major or nonmajor clinically relevant bleeding was significantly higher in the East Asian cohort than in the remaining study population, irrespective of treatment assignment (HR=1.42; 95% CI, 1.25–1.62; P<0.0001; Table 4). However, there was no significant difference in the risk of major bleeding between patients residing within versus outside East Asia, irre-spective of treatment regimen (HR=1.23; 95% CI, 0.94–1.60; P=0.14; Figure 2). For most bleeding outcomes, the safety profile of rivaroxaban versus warfarin was consistent among ROCKET AF patients resident within and outside East Asia (Figure 2).

Overall, there were 108 (23.2%) and 144 (31.2%) non-bleeding treatment-emergent serious adverse events in the rivaroxaban and warfarin treatment groups, respectively, in the ROCKET AF East Asian cohort (Table II in the online-only Data Supplement). The most common adverse event was car-diac failure, occurring in 9 (1.9%) patients in the rivaroxaban group and 16 (3.5%) patients in the warfarin group. Dyspnea was reported as a treatment-emergent nonserious adverse event by 28 patients in each of the rivaroxaban (6.0%) and warfarin (6.1%) treatment groups.

DiscussionIn this regional analysis of ROCKET AF, we assessed the effi-cacy and safety of rivaroxaban versus warfarin among East

Asian patients and compared results with those from ROCKET AF patients recruited outside East Asia. Although event rates were higher among East Asian patients, the relative efficacy and safety of rivaroxaban versus warfarin was similar to that of non–East Asian patients. The significant interaction between treatment group and prior ASA use in the ROCKET AF East Asian cohort for the principal safety outcome could be caused by the risk profile of the East Asian population. However, the observed interaction P value has not been corrected for multiple analyses and could also be a chance finding. Therefore, although patient numbers were relatively low in the East Asian cohort, these results support extrapolation of the full trial results to the East Asian patient population.

Analysis of the baseline demographics confirms much of what was previously known about the population of East Asia. The mean body weight and BMI of patients in the East Asian cohort were lower than those of the other patients in ROCKET AF; previous studies have also shown body weight and BMI to be lower in Asian than in white populations.2,6 This is an impor-tant finding when analyzing the efficacy and safety results for the ROCKET AF East Asian cohort and the remaining ROCKET AF population because it is consistent with previous observa-tions showing that rivaroxaban can be used without dose adjust-ment for body weight.18,19 Patients in the ROCKET AF East Asian cohort had higher levels of prior stroke/TIA/non-CNS systemic embolism compared with the remaining study popula-tion, a finding supported by a recent publication that reported a higher burden of stroke relative to ischemic heart disease in East Asia.20 Conversely, fewer patients in the East Asian cohort had other risk factors for stroke (hypertension, congestive heart failure, diabetes mellitus). There was also a higher number of VKA-naive patients in the ROCKET AF East Asian cohort, which is in line with other data from the region that suggest that warfarin is underused.11 Irrespective of treatment assignment, patients in the East Asian cohort had significantly higher lev-els of major or nonmajor clinically relevant bleeding and there was a strong trend toward increased rates of stroke or systemic embolism versus the remaining ROCKET AF study population. One possible explanation is that patients in the East Asian cohort had higher levels of baseline prior stroke/TIA/nonsystemic embolism compared with the remaining study population; it has been shown that patients with AF and with prior stroke or TIA have higher absolute rates of stroke or systemic embolism than patients with AF without prior stroke or TIA.21 However, the risk of major bleeding was not significantly higher in the East Asian cohort than in the remaining study population, irrespective of whether they received warfarin or rivaroxaban.

For the primary efficacy end point in the ROCKET AF East Asian cohort, no interaction between the treatment effect of rivaroxaban versus warfarin and cTTR quartiles was apparent (Table 3), suggesting that the efficacy of rivaroxaban versus warfarin is not affected by the quality of warfarin manage-ment. However, care should be taken in interpreting these data because of the low numbers of patients in the East Asian cohort and the corresponding low number of efficacy events.

In analyzing the results for the secondary efficacy end points in the ROCKET AF East Asian cohort (Figure 1), the observed reduction in hemorrhagic stroke with rivaroxaban

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1746 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 non–East Asian patients. In contrast, there was no significant difference in the rate of intracranial hemorrhage in East Asian versus non–East 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 population—the 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 30–49 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,

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Wong et al Rivaroxaban for Stroke Prevention 1747

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.

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ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–891.

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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;8:150–154.

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;14:328–369.

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;159:340–347.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;75:1328–1333.

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;76:2104–2111.

17. Rosendaal FR, Cannegieter SC, van der Meer FJ, Briët E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost. 1993;69:236–239.

18. Mueck W, Eriksson BI, Bauer KA, Borris L, Dahl OE, Fisher WD, et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban–an oral, direct factor Xa inhibitor–in patients undergoing major orthopaedic surgery. Clin Pharmacokinet. 2008;47:203–216.

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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;11:315–322.

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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):e531S–e575S.

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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;44:1891–1896.

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;369:2093–2104.

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on behalf of The Executive Steering Committee and the ROCKET AF Study InvestigatorsA.A. Fox, Scott D. Berkowitz, Werner Hacke and Graeme J. Hankey

E. Singer, Günter Breithardt, Kenneth W. Mahaffey, Richard C. Becker, Robert Califf, Keith Ka Sing Lawrence Wong, Dai Yi Hu, Abraham Oomman, Ru-San Tan, Manesh R. Patel, Daniel

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

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1

SUPPLEMENTARY MATERIALS

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

Professor Ka Sing Lawrence Wong on behalf of The Executive Steering Committee and the ROCKET AF Study Investigators

Table of contents

Supplementary Tables.......................................................................................................... 2 

Supplementary Table I. Intracranial hemorrhage: patients from East Asian versus non-East Asian patients within each treatment group……………………………………………….2

Supplementary Table II. Most frequent non-hemorrhagic serious treatment-emergent adverse events in the ROCKET AF East Asian cohort.* ..................................................... 3 

Supplementary Figures ........................................................................................................ 5 

Supplementary figure I. ROCKET AF East Asian cohort flow diagram. .............................. 5 

Supplementary figure II. Subgroup analyses for the primary efficacy endpoint in the intention-to-treat population until site notification of the ROCKET AF East Asian cohort.... 6 

Supplementary figure III. Subgroup analyses for the principal safety outcome in the safety population during treatment of the ROCKET AF East Asian cohort. ................................... 8 

Supplementary figure IV. Subgroup analyses for major bleeding in the safety population during treatment of the ROCKET AF East Asian cohort.................................................... 10 

2

Supplementary Tables

Supplementary Table I. Intracranial hemorrhage: patients from East

Asian versus non-East Asian patients within each treatment group.

Treatment group East Asia vs non-East Asia

Hazard ratio (95% CI)*

Rivaroxaban 1·20

(0·43 to 3·31); P=0·73

Warfarin 3·89

(2·29 to 6·63); P<0·0001

*Safety population during treatment.

Event rates are shown in Figure 2.

CI, confidence interval.

3

Supplementary Table II. Most frequent non-hemorrhagic serious

treatment-emergent adverse events in the ROCKET AF East Asian

cohort.*

Rivaroxaban (N=466) n (%)

Warfarin (N=462) n (%)

Total patients with non-bleeding treatment-emergent serious adverse event†

108 (23.2) 144 (31.2)

Cardiac failure 9 (1.9) 16 (3.5)

Pneumonia 7 (1.5) 8 (1.7)

Cardiac failure congestive 5 (1.1) 10 (2.2)

Lung infection 5 (1.1) 3 (0.6)

Atrial fibrillation 4 (0.9) 7 (1.5)

Coronary artery disease 4 (0.9) 2 (0.4)

Dental caries 4 (0.9) 1 (0.2)

Colon cancer 3 (0.6) 1 (0.2)

Colonic polyp 3 (0.6) 1 (0.2)

Hyperglycemia 3 (0.6) 2 (0.4)

Pleural effusion 3 (0.6) 0 (0.0)

Sudden death 3 (0.6) 2 (0.4)

Urinary tract infection 3 (0.6) 2 (0.4)

Angina pectoris 2 (0.4) 2 (0.4)

Bronchitis 2 (0.4) 3 (0.6)

Cardiogenic shock 2 (0.4) 0 (0.0)

Femoral neck fracture 2 (0.4) 2 (0.4)

Gastroenteritis 2 (0.4) 2 (0.4)

Hypoglycemia 2 (0.4) 1 (0.2)

4

Intervertebral disc protrusion 2 (0.4) 0 (0.0)

Lower respiratory tract infection 2 (0.4) 0 (0.0)

Lung neoplasm malignant 2 (0.4) 1 (0.2)

Spinal compression fracture 2 (0.4) 1 (0.2)

Syncope 2 (0.4) 3 (0.6)

Upper respiratory tract infection 2 (0.4) 1 (0.2)

ALT >3 × ULN and TBL >2 × ULN either on same day or within following 30 days‡

3 (0.7) 5 (1.1)

Based on safety population. *Most frequent based on the rivaroxaban treatment group. †Events that started on or after the first dose of study medication and up to 2 days after the last dose of study medication. ‡Prespecified laboratory abnormalities not included in the list of the 15 most frequent non-hemorrhagic treatment-emergent serious adverse events. ALT, alanine aminotransferase; TBL, total bilirubin; ULN, upper limit of normal.

5

Supplementary Figures

Supplementary figure I. ROCKET AF East Asian cohort flow diagram.

6

Supplementary figure II. Subgroup analyses for the primary efficacy endpoint

in the intention-to-treat population until site notification of the ROCKET AF

East Asian cohort.

This is a post hoc analysis that has not been corrected for multiple analyses. Interpretation of the interaction P-values requires consideration of the lack of a significant treatment effect between the two treatment groups. Hazard ratios displayed in the forest plots are calculated from event rates (%/year) whereas the numbers of events shown at left indicate the percentage of patients experiencing an event (n/N). *Hazard ratio (95% CI) from the Cox proportional hazard model with treatment as a covariate. †P-value for the interaction of treatment group and each baseline subgroup based on the Cox proportional hazard model, including treatment group, baseline, subgroup, and their interaction. Statistically significant at nominal 0.05 (two-sided). ASA, acetylsalicylic acid; CI, confidence interval; CNS, central nervous system; TIA, transient ischemic attack.

7

8

Supplementary figure III. Subgroup analyses for the principal safety outcome in

the safety population during treatment of the ROCKET AF East Asian cohort.

This is a post hoc analysis that has not been corrected for multiple analyses. Interpretation of the interaction P-values requires consideration of the lack of a significant treatment effect between the two treatment groups. Hazard ratios displayed in the forest plots are calculated from event rates (%/year) whereas the numbers of events shown at left indicate the percentage of patients experiencing an event (n/N). *Hazard ratio (95% CI) from the Cox proportional hazard model with treatment as a covariate. †P-value for the interaction of treatment group and each baseline subgroup based on the Cox proportional hazard model, including treatment group, baseline subgroup, and their interaction. Statistically significant at nominal 0.05 (two-sided). ASA, acetylsalicylic acid; CI, confidence interval; CNS, central nervous system; TIA, transient ischemic attack.

9

10

Supplementary figure IV. Subgroup analyses for major bleeding in the safety

population during treatment of the ROCKET AF East Asian cohort.

This is a post hoc analysis that has not been corrected for multiple analyses. Interpretation of the interaction P-values requires consideration of the lack of a significant treatment effect between the two treatment groups. Hazard ratios displayed in the forest plots are calculated from event rates (%/year) whereas the numbers of events shown at left indicate the percentage of patients experiencing an event (n/N). *Hazard ratio (95% CI) from the Cox proportional hazard model with treatment as a covariate. †P-value for the interaction of treatment group and each baseline subgroup based on the Cox proportional hazard model, including treatment group, baseline subgroup, and their interaction. Statistically significant at nominal 0.05 (two-sided). ASA, acetylsalicylic acid; CI, confidence interval; CNS, central nervous system; TIA, transient ischemic attack.

11