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

Transcription

1 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 Downloaded from by guest on July 1, 2018 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 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: Unique identifier: NCT (Stroke. 2014;45: ) Key Words: atrial fibrillation Far East rivaroxaban stroke See related article, p 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 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 creatinine clearance [CrCl] of ml/min) was noninferior 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 Received July 25, 2013; final revision received February 8, 2014; accepted February 27, 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 /-/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. ks-wong@cuhk.edu.hk 2014 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 1740 Stroke June 2014 Downloaded from by guest on July 1, 2018 not significantly different between the 2 study groups; however, intracranial hemorrhage and fatal bleeding occurred significantly 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 evidence 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 supplements 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 underprescribed 11,12 or underdosed 13 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, outcomes 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 international normalized ratio (INR) range of 2.0 to 3.0. Methods Overview of the ROCKET AF Study The 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 rivaroxaban 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 ml/min) or adjusted-dose warfarin (target INR, ). 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 defined as clinically overt bleeding associated with any of the following: fatal bleeding, critical organ bleeding, hemoglobin drop 2 g/dl, or transfusions of 2 U of whole blood or packed red blood cells. Analysis of the East Asian Cohort of ROCKET AF A 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 representative 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 Demographics Baseline 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 Analyses The 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% confidence 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 outcomes. HRs for patients residing within versus outside East Asia, irrespective 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 treatment, 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 secondary efficacy end points and safety outcomes was also assessed. For selected significant interactions, HRs for patients residing within versus 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 al 17 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 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

3 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. Results Patient Recruitment A 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 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 follow-up period was 668 days. This compares with 593 and 708 days, respectively, in the remaining study population. Patient Baseline Demographics Baseline 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 Downloaded from by guest on July 1, 2018 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 Mean baseline weight, kg Median BMI, kg/m Baseline mean creatinine clearance, ml/min Prior vitamin K antagonist use, % Prior chronic ASA use, % Baseline congestive heart failure, % Baseline diabetes mellitus, % Baseline hypertension, % Prior stroke/tia/non-cns systemic embolism, % Prior myocardial infarction Mean baseline CHADS 2 score CHA 2 DS 2 -VASc, % < CHA 2 DS 2 -VASc, mean HAS-BLED, % HAS-BLED, mean Time within 1.5 <2.0, % Time within , % ASA indicates acetylsalicylic acid; BMI, body mass index; CHADS 2, congestive heart failure, hypertension, age, diabetes, prior stroke/tia; CHA 2 DS 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.

4 1742 Stroke June 2014 Downloaded from by guest on July 1, 2018 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 Factor Xa Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation. *Hazard 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. Statistically significant at nominal 0.05 (2-sided). 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%; 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 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 population (rivaroxaban, 44.7%; warfarin, 43.3%). Efficacy End Points In the East Asian cohort, the observed annual event rates for the primary efficacy end point of stroke or systemic embolism were numerically higher (2.6% and 3.4% per year in the rivaroxaban and warfarin arms, respectively [HR=0.78; 95% CI, ]) compared with corresponding annual rates in the remaining ROCKET AF population (2.1% and 2.4% per year [HR=0.89; 95% CI, ]). However, no significant interaction between treatment and residential status was identified (P=0.666; Figure 1 and Table 2). The efficacy of

5 Wong et al Rivaroxaban for Stroke Prevention 1743 Table 2. Primary Efficacy End Point of Stroke or Systemic Embolism in the Intention-to-Treat Population Until Site Notification* Analysis Method n/n Rivaroxaban Warfarin Rivaroxaban vs Warfarin Event Rate, % per Year n/n Event Rate, % per Year Hazard Ratio (95% CI) Interaction P Value East Asia vs Non East Asia Hazard Ratio (95% CI) ROCKET AF East Asian cohort 21/ / ( ) ( ); ROCKET AF (excluding East Asia) 248/ / ( ) P=0.053 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). Downloaded from by guest on July 1, 2018 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 secondary efficacy end points (stroke, non-cns systemic embolism, 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, ). Observed rates of all-cause mortality were also nonsignificantly lower with rivaroxaban (2.6% per year) than with warfarin (3.6% per year [HR=0.73; 95% CI, ]), 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, ]). 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 population irrespective of treatment assignment (HR=1.34; 95% CI, ; P=0.053; Table 2). Observed annual rates of all-cause stroke, hemorrhagic stroke, ischemic stroke, nondisabling 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 interaction 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 identified for the other secondary efficacy end points (non-cns systemic embolism; myocardial infarction; all-cause, vascular, and nonvascular death; Figure 1). INR and cttr Analyses Among warfarin-treated patients in the ROCKET AF East Asian cohort, patient INR values were within the therapeutic range ( ) 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 3. Primary Efficacy Treatment Effect by Quartiles of Center Time in Therapeutic Range in the ROCKET AF East Asian Cohort* Rivaroxaban Warfarin cttr,% n/n (%) Event Rate, % per Year n/n (%) Event Rate, % per Year Rivaroxaban vs Warfarin HR (95% CI) /114 (2.6) 2.0 3/115 (2.6) ( ) /109 (1.8) 1.2 5/107 (4.7) ( ) /119 (3.4) 2.4 9/113 (8.0) ( ) /112 (4.5) 2.9 6/127 (4.7) ( ) 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= International normalized ratio, 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.

6 1744 Stroke June 2014 Table 4. Principal Safety Outcome of Major or Nonmajor Clinically Relevant Bleeding in the Safety Population During Treatment Cohort ROCKET AF East Asian cohort ROCKET AF (excluding East Asia) n/n Rivaroxaban Warfarin Rivaroxaban vs Warfarin Event Rate, % per Year n/n Event Rate, % per Year Hazard Ratio (95% CI) Interaction P Value East Asia vs Non East Asia* Hazard Ratio (95% CI) 121/ / ( ) ( ); P< / / ( ) 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). Downloaded from by guest on July 1, 2018 With regard to cttr, no interaction with treatment effect was apparent when assessing rivaroxaban for the primary efficacy end point in the East Asian cohort (P=0.585 for interaction; Table 3). Safety Outcomes In the ROCKET AF East Asian cohort, the annual event rates for major or nonmajor clinically relevant bleeding (the principal safety outcome) were 20.9% and 20.7% per year in the rivaroxaban and warfarin arms, respectively (HR=1.01; 95% CI, ; Table 4). This compares with 14.5% and 14.1%, respectively, per year in the ROCKET AF population excluding East Asia (HR=1.03; 95% CI, ). However, no significant 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 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 Factor Xa Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation. *Hazard 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. Statistically 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, ; P=0.14). Bleeding events were considered to be critical if they occurred in intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular (with compartment syndrome), or retroperitoneal sites. See Table I in the online-only Data Supplement.

7 Wong et al Rivaroxaban for Stroke Prevention 1745 Downloaded from by guest on July 1, 2018 significant interactions between treatment group and any prespecified 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 onlineonly Data Supplement). Rivaroxaban was also associated with reductions in critical organ bleeding and intracranial hemorrhage relative to warfarin 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, ). Rates of intracranial hemorrhage 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, ). 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 receiving rivaroxaban, there was no significant difference in the rate of intracranial hemorrhage for East Asians versus non East Asians (HR=1.20; 95% CI, ; 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, ; P<0.0001; Table I in the online-only Data Supplement). Among East Asian patients, there were 20 events with hemoglobin 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, ). 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, ]). 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, ; 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, irrespective of treatment regimen (HR=1.23; 95% CI, ; 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%) nonbleeding 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 cardiac 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. Discussion In this regional analysis of ROCKET AF, we assessed the efficacy 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 important 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 observations showing that rivaroxaban can be used without dose adjustment 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 population, 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 levels 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 management. 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

8 1746 Stroke June 2014 Downloaded from by guest on July 1, 2018 versus warfarin is an important finding given the concern over the higher rates of hemorrhagic stroke and intracranial hemorrhage in Asian populations. Although statistical significance was not attained for the East Asian results, the results are consistent with the nominally significant results for patients outside 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 underprescribed 11,12 or underdosed 13 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 administered 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 administering 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 intracranial hemorrhage in East Asian patients receiving warfarin versus 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 intracranial 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, warfarin has been shown to interact with some herbal products that are commonly used in the Asia-Pacific region. The risk of bleeding 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 relatively 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 versus 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 dabigatran 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 warfarin 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 Limitations When 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 various outcomes and can make extrapolation of the results difficult. 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. Conclusions Several 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 compared 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 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. Acknowledgments We thank Michael Barton who provided medical writing services with funding from Janssen Scientific Affairs, LLC, and Bayer HealthCare Pharmaceuticals. Sources of Funding The ROCKET study was funded by Janssen Research and Development, LLC, and Bayer HealthCare Pharmaceuticals. Disclosures Dr Wong has received honoraria as a member of a steering committee 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,

9 Wong et al Rivaroxaban for Stroke Prevention 1747 Downloaded from by guest on July 1, 2018 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 advisory 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 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 consulting 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 listed at 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 committee 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 honoraria 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: 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:e 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). 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10 Rivaroxaban for Stroke Prevention in East Asian Patients From the ROCKET AF Trial Ka Sing Lawrence Wong, Dai Yi Hu, Abraham Oomman, Ru-San Tan, Manesh R. Patel, Daniel E. Singer, Günter Breithardt, Kenneth W. Mahaffey, Richard C. Becker, Robert Califf, Keith A.A. Fox, Scott D. Berkowitz, Werner Hacke and Graeme J. Hankey on behalf of The Executive Steering Committee and the ROCKET AF Study Investigators Downloaded from by guest on July 1, 2018 Stroke. 2014;45: ; originally published online April 24, 2014; doi: /STROKEAHA Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX Copyright 2014 American Heart Association, Inc. All rights reserved. Print ISSN: Online ISSN: The online version of this article, along with updated information and services, is located on the World Wide Web at: Data Supplement (unedited) at: Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: Subscriptions: Information about subscribing to Stroke is online at: