Efficacy and Safety of Rivaroxaban for the Prevention of Stroke in Subjects With Non-Valvular Atrial Fibrillation

Evaluation of the Efficacy and Safety of Rivaroxaban (BAY59-7939) for the Prevention of Stroke and Non-central Nervous System Systemic Embolism in Subjects With Non-valvular Atrial Fibrillation

This is a clinical study evaluating the efficacy and safety of rivaroxaban for stroke prevention in patients with atrial fibrillation (originally described in Japanese).

Study Overview

• Status: Completed
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: Rivaroxaban (Xarelto, BAY59-7939); Drug: Warfarin placebo; Drug: Warfarin; Drug: Rivaroxaban placebo

Detailed Description

Within the US 'Johnson & Johnson Pharmaceutical Research & Development, L.L.C.' is sponsor.

• Study Type: Interventional
• Enrollment (Actual): 1280
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Fukui, Japan, 910-0067
  • Fukuoka, Japan, 810-8563
  • Fukuoka, Japan, 811-0213
  • Fukuoka, Japan, 813-0044
  • Fukuoka, Japan, 814-0180
  • Gifu, Japan, 500-8225
  • Kagoshima, Japan, 891-0116
  • Kumamoto, Japan, 860-0008
  • Kyoto, Japan, 602-8026
  • Nagasaki, Japan, 850-8555
  • Oita, Japan, 870-0021
  • Oita, Japan, 870-0192
  • Oita, Japan, 870-0263
  • Oita, Japan, 870-0917
  • Okayama, Japan, 700-8558
  • Okayama, Japan, 700-8607
  • Okinawa, Japan, 904-8585
  • Osaka, Japan, 530-0001
  • Osaka, Japan, 530-8480
  • Osaka, Japan, 537-0011
  • Osaka, Japan, 540-0006
  • Osaka, Japan, 558-0011
  • Osaka, Japan, 558-8558
  • Shizuoka, Japan, 421-0193
  • Shizuoka, Japan, 422-8527
  • Shizuoka, Japan, 424-8636
  • Tokushima, Japan, 770-0011
  • Tottori, Japan, 689-0203
  • Toyama, Japan, 930-0194
  • Wakayama, Japan, 640-8505
  • Aichi
    • Kasugai, Aichi, Japan, 487-0013
    • Nagoya, Aichi, Japan, 453-8511
    • Nagoya, Aichi, Japan, 454-8502
    • Nagoya, Aichi, Japan, 455-8530
    • Nagoya, Aichi, Japan, 457-8510
    • Nagoya, Aichi, Japan, 462-0825
    • Okazaki, Aichi, Japan, 444-8553
  • Aomori
    • Goshogawara, Aomori, Japan, 037-0053
    • Hirosaki, Aomori, Japan, 036-8082
    • Hirosaki, Aomori, Japan, 036-8545
  • Chiba
    • Asahi, Chiba, Japan, 289-2511
    • Funabashi, Chiba, Japan, 274-8503
    • Imba, Chiba, Japan, 270-1694
    • Matsudo, Chiba, Japan, 270-2251
    • Matsudo, Chiba, Japan, 271-0077
    • Yotsukaido, Chiba, Japan, 284-0032
  • Ehime
    • Imabari, Ehime, Japan, 799-1592
    • Matsuyama, Ehime, Japan, 790-0024
    • Matsuyama, Ehime, Japan, 790-0925
    • Matsuyama, Ehime, Japan, 791-8026
    • Niihama, Ehime, Japan, 792-8543
    • Saijo, Ehime, Japan, 793-0030
    • Toon, Ehime, Japan, 791-0281
  • Fukuoka
    • Chikushi-gun, Fukuoka, Japan, 811-1244
    • Chikushino, Fukuoka, Japan, 818-8502
    • Chikushino, Fukuoka, Japan, 818-8516
    • Kasuga, Fukuoka, Japan, 816-0833
    • Kasuga, Fukuoka, Japan, 816-0864
    • Kitakyushu, Fukuoka, Japan, 800-0057
    • Kitakyushu, Fukuoka, Japan, 806-8501
    • Kurume, Fukuoka, Japan, 830-8577
    • Ogori, Fukuoka, Japan, 838-0141
    • Yame, Fukuoka, Japan, 834-0004
    • Yame, Fukuoka, Japan, 834-0006
  • Fukushima
    • Koriyama, Fukushima, Japan, 963-8052
  • Gifu
    • Ogaki, Gifu, Japan, 503-8502
  • Gunma
    • Maebashi, Gunma, Japan, 371-8511
    • Mebashi, Gunma, Japan, 371-0014
  • Hiroshima
    • Otake, Hiroshima, Japan, 739-0696
  • Hokkaido
    • Asahikawa, Hokkaido, Japan, 078-8214
    • Chitose, Hokkaido, Japan, 066-0034
    • Hakodate, Hokkaido, Japan, 040-8611
    • Muroran, Hokkaido, Japan, 051-8501
    • Otaru, Hokkaido, Japan, 047-8510
    • Sapporo, Hokkaido, Japan, 004-0052
    • Sapporo, Hokkaido, Japan, 060-0033
    • Sapporo, Hokkaido, Japan, 060-0061
    • Sapporo, Hokkaido, Japan, 060-8570
    • Sapporo, Hokkaido, Japan, 064-0807
    • Sapporo, Hokkaido, Japan, 064-8570
    • Sapporo, Hokkaido, Japan, 065-0027
    • Sapporo, Hokkaido, Japan, 065-0033
    • Sapporo, Hokkaido, Japan, 065-8611
    • Sunagawa, Hokkaido, Japan, 073-0196
    • Tomakomai, Hokkaido, Japan, 053-8506
  • Hyogo
    • Kobe, Hyogo, Japan, 651-0073
    • Kobe, Hyogo, Japan, 651-1145
    • Kobe, Hyogo, Japan, 652-0803
  • Ibaraki
    • Higashiibaraki, Ibaraki, Japan, 311-3193
    • Hitachi, Ibaraki, Japan, 317-0077
    • Joso, Ibaraki, Japan, 303-0016
    • Kasama, Ibaraki, Japan, 309-1793
    • Moriya, Ibaraki, Japan, 302-0112
    • Namegata, Ibaraki, Japan, 311-3516
    • Toride, Ibaraki, Japan, 302-0022
  • Ishikawa
    • Kanazawa, Ishikawa, Japan, 920-8650
    • Nomi, Ishikawa, Japan, 923-1100
  • Iwate
    • Hanamaki, Iwate, Japan, 025-0075
    • Morioka, Iwate, Japan, 020-0103
  • Kagawa
    • Marugame, Kagawa, Japan, 763-8502
    • Takamatsu, Kagawa, Japan, 760-0018
  • Kagoshima
    • Izumi, Kagoshima, Japan, 899-0131
  • Kanagawa
    • Atsugi, Kanagawa, Japan, 243-8551
    • Fujisawa, Kanagawa, Japan, 251-0041
    • Fujisawa, Kanagawa, Japan, 251-8550
    • Kamakura, Kanagawa, Japan, 247-8533
    • Kawasaki, Kanagawa, Japan, 216-8511
    • Yokohama, Kanagawa, Japan, 227-0046
    • Yokohama, Kanagawa, Japan, 231-8682
    • Yokohama, Kanagawa, Japan, 236-0037
    • Yokohama, Kanagawa, Japan, 236-0051
  • Kochi
    • Nangoku, Kochi, Japan, 783-8509
  • Kyoto
    • Uji, Kyoto, Japan, 611-0042
  • Mie
    • Kuwana, Mie, Japan, 511-0068
  • Miyagi
    • Sendai, Miyagi, Japan, 980-0803
    • Sendai, Miyagi, Japan, 981-3107
    • Sendai, Miyagi, Japan, 983-0821
    • Sendai, Miyagi, Japan, 983-8512
    • Sendai, Miyagi, Japan, 983-8520
  • Nagano
    • Komoro, Nagano, Japan, 384-8588
    • Matsumoto, Nagano, Japan, 390-8510
    • Suwa, Nagano, Japan, 392-8510
  • Niigata
    • Joetsu, Niigata, Japan, 949-3193
    • Nagaoka, Niigata, Japan, 940-8621
  • Oita
    • Beppu, Oita, Japan, 874-0011
    • Beppu, Oita, Japan, 874-0901
    • Yufu, Oita, Japan, 879-5593
  • Okayama
    • Kasaoka, Okayama, Japan, 714-0043
  • Okinawa
    • Shimajiri, Okinawa, Japan, 901-0493
  • Osaka
    • Daito, Osaka, Japan, 574-0074
    • Higashiosaka, Osaka, Japan, 578-8588
    • Hirakata, Osaka, Japan, 573-0153
    • Hirakata, Osaka, Japan, 573-8511
    • Kawachinagano, Osaka, Japan, 586-8521
    • Kishiwada, Osaka, Japan, 596-8522
    • Takatsuki, Osaka, Japan, 569-1096
    • Toyonaka, Osaka, Japan, 560-0022
    • Yao, Osaka, Japan, 581-0011
  • Saitama
    • Hanyu, Saitama, Japan, 348-8505
    • Kasukage, Saitama, Japan, 344-0035
    • Kitamoto, Saitama, Japan, 364-8501
    • Tokorozawa, Saitama, Japan, 359-1141
    • Tokorozawa, Saitama, Japan, 359-1142
    • Wako, Saitama, Japan, 351-0102
  • Shiga
    • Kusatsu, Shiga, Japan, 525-8585
  • Shizuoka
    • Fujinomiya, Shizuoka, Japan, 418-0076
    • Fukuroi, Shizuoka, Japan, 437-0061
    • Hamamatsu, Shizuoka, Japan, 432-8580
    • Hamamatsu, Shizuoka, Japan, 433-8558
    • Iwata, Shizuoka, Japan, 438-8550
    • Shimada, Shizuoka, Japan, 427-8502
  • Tokushima
    • Naruto, Tokushima, Japan, 772-8503
  • Tokyo
    • Edogawa-ku, Tokyo, Japan, 133-0052
    • Hachioji, Tokyo, Japan, 192-0045
    • Higashikurume, Tokyo, Japan, 203-0033
    • Itabashi-ku, Tokyo, Japan, 173-8610
    • Itabashi-ku, Tokyo, Japan, 175-0082
    • Meguro-ku, Tokyo, Japan, 153-8515
    • Ota-ku, Tokyo, Japan, 145-0065
    • Shibuya-ku, Tokyo, Japan, 150-0013
    • Shinagawa-ku, Tokyo, Japan, 141-0001
    • Shinjuku-ku, Tokyo, Japan, 162-8655
  • Yamagata
    • Higashikawada, Yamagata, Japan, 999-7782
  • Yamaguchi
    • Shimonoseki, Yamaguchi, Japan, 750-0061
    • Shunan, Yamaguchi, Japan, 745-8522

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 20 years or older
• Japanese male or female
• Non- valvular atrial fibrillation documented by ECG
• Patients with a risk of stroke and non-CNS systemic embolism

Exclusion Criteria:

• Significant mitral stenosis
• Patients in whom anticoagulants are contraindicated

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rivaroxaban (Xarelto, BAY59-7939); Participants received once daily (OD) a rivaroxaban 15 mg tablet and a warfarin placebo tablet during the double-blind treatment period	Drug: Rivaroxaban (Xarelto, BAY59-7939); Participants orally administered rivaroxaban 15 mg OD (CrCL [creatinine clearance] >= 50 mL/min) or 10 mg OD (CrCL 30-49 mL/min); Drug: Warfarin placebo; Participants orally administered a warfarin placebo tablet (adjusted based upon sham INR values)
Active Comparator: Warfarin; Participants received OD a warfarin potassium tablet and a rivaroxaban placebo tablet during the double-blind treatment period	Drug: Warfarin; Participants orally administered a warfarin potassium tablet (INR [international normalized ratio] target was 1.6-2.6 for patients >70 years and 2.0-3.0 for patients <70 years); Drug: Rivaroxaban placebo; Participants orally administered a rivaroxaban placebo tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event Rate of the Composite Endpoint of Adjudicated Major Bleeding or Adjudicated Non-major Clinically Relevant Bleeding	Major bleeding: clinically overt bleeding (COB) associated with a fall in hemoglobin ≥2 g/dL, leading to transfusion ≥2 units of packed red blood cells or whole blood, occurring in a critical site or contributing to death. Non-major clinically relevant bleeding: COB that does not meet the definition of major bleeding, but requires medical intervention or unscheduled contact with the physician, (temporary) discontinuation of the study treatment, discomfort to the subject such as pain, or impairment of activities of daily life.	Up to 2 days after the last dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event Rate of the Composite Endpoint of Adjudicated Stroke and Non-central Nervous System (CNS) Systemic Embolism	This is the principal efficacy endpoint. Stroke included hemorrhagic, ischemic infarction and unknown. Arterial emboli in the following areas were "non-CNS systemic embolism": peripheral arterial in the upper and lower extremities, renal, mesenteric, splenic, hepatic, ocular/retinal and others. Pulmonary embolism or myocardial infarction was excluded.	Up to 2 days after the last dose
Event Rate of the Composite Endpoint of Adjudicated Stroke, Non-CNS Systemic Embolism, and Vascular Death	Stroke included hemorrhagic, ischemic infarction and unknown. Arterial emboli in the following areas were "non-CNS systemic embolism": peripheral arterial in the upper and lower extremities, renal, mesenteric, splenic, hepatic, ocular/retinal and others. Pulmonary embolism or myocardial infarction was excluded. Any death that was not clearly non-vascular.	Up to 2 days after the last dose
Event Rate of the Composite Endpoint of Adjudicated Stroke, Non-CNS Systemic Embolism, Myocardial Infarction, and Vascular Death	Stroke included hemorrhagic, ischemic infarction and unknown. Arterial emboli in the following areas were "non-CNS systemic embolism": peripheral arterial in the upper and lower extremities, renal, mesenteric, splenic, hepatic, ocular/retinal and others. Pulmonary embolism or myocardial infarction was excluded. Myocardial infarction: assessed based on either cardiac biomarkers, new abnormal Q waves appeared on electrocardiogram for ≥2 leads, or autopsy confirmation. Any death that was not clearly non-vascular.	Up to 2 days after the last dose
Event Rate of Stroke	All events were adjudicated and confirmed by a central independent committee blinded to treatment. Stroke included hemorrhagic (Stroke with local collections of intraparenchymal blood. Subarachnoid hemorrhage, subdural hemorrhage, and epidural hemorrhage were excluded.), ischemic infarction (Stroke without focal collection of intracranial blood) and unknown (No imaging data and anatomic findings were available.).	Up to 2 days after the last dose
Event Rate of Non-CNS Systemic Embolism	All events were adjudicated and confirmed by a central independent committee blinded to treatment. Non-CNS systemic embolism was abrupt vascular insufficiency associated with clinical or radiological evidence of arterial occlusion in the absence of other likely mechanisms (such as trauma, atherosclerosis, and instrumentation). Arterial emboli in the following areas were "non-CNS systemic embolism": peripheral arterial in the upper and lower extremities, renal, mesenteric, splenic, hepatic, ocular/retinal and others. Pulmonary embolism or myocardial infarction was excluded from this category.	Up to 2 days after the last dose
Event Rate of Myocardial Infarction	All events were adjudicated and confirmed by a central independent committee blinded to treatment. Myocardial infarction was assessed based on either cardiac bio-markers (troponin I, troponin T, or creatine kinase-muscle and brain subunit isozyme), new abnormal Q waves appeared on ECG for 2 or more leads, or autopsy confirmation.	Up to 2 days after the last dose
Event Rate of Vascular Death	All events were adjudicated and confirmed by a central independent committee blinded to treatment. Any death that was not clearly non-vascular (e.g., deaths due to spontaneous bleeding, myocardial infarction, stroke, cardiac failure, and arrhythmia)	Up to 2 days after the last dose
Event Rate of Stroke With Serious Residual Disability	All events were adjudicated and confirmed by a central independent committee blinded to treatment. A stroke was considered disabling if the participant's modified Rankin score was between 3 and 5, inclusive.	Up to 2 days after the last dose
Event Rate of All-cause Death	All events were adjudicated and confirmed by a central independent committee blinded to treatment. All-cause death included vascular death and non-vascular death.	Up to 2 days after the last dose
Event Rate of Adjudicated Major Bleeding	All events were adjudicated and confirmed by a central independent committee blinded to treatment. Major bleeding was clinically overt bleeding associated with a fall in hemoglobin of 2 g/dL or higher, leading to a transfusion of 2 or more units of packed red blood cells or whole blood, occurring in a critical site or contributing to death.	Up to 2 days after the last dose
Event Rate Adjudicated Non-major Clinically Relevant Bleeding	All events were adjudicated and confirmed by a central independent committee blinded to treatment. Non-major clinically relevant bleeding was clinically overt bleeding that does not meet the definition of major bleeding, but requires medical intervention or unscheduled contact with the physician, (temporary) discontinuation of the study treatment, discomfort to the subject such as pain, or impairment of activities of daily life.	Up to 2 days after the last dose

Collaborators and Investigators

• Sponsor: Bayer
• Collaborators: Janssen R&D, L.L.C.

Publications and helpful links

General Publications

• Hori M, Matsumoto M, Tanahashi N, Momomura S, Uchiyama S, Goto S, Izumi T, Koretsune Y, Kajikawa M, Kato M, Ueda H, Iwamoto K, Tajiri M; J-ROCKET AF study investigators. Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation - the J-ROCKET AF study -. Circ J. 2012;76(9):2104-11. doi: 10.1253/circj.cj-12-0454. Epub 2012 Jun 5.
• Chan MY, Lin M, Lucas J, Moseley A, Thompson JW, Cyr D, Ueda H, Kajikawa M, Ortel TL, Becker RC. Plasma proteomics of patients with non-valvular atrial fibrillation on chronic anti-coagulation with warfarin or a direct factor Xa inhibitor. Thromb Haemost. 2012 Dec;108(6):1180-91. doi: 10.1160/TH12-05-0310. Epub 2012 Oct 10.
• Tanahashi N, Hori M, Matsumoto M, Momomura S, Uchiyama S, Goto S, Izumi T, Koretsune Y, Kajikawa M, Kato M, Ueda H, Iwamoto K, Tajiri M; J-ROCKET AF Study Investigators. Rivaroxaban versus warfarin in Japanese patients with nonvalvular atrial fibrillation for the secondary prevention of stroke: a subgroup analysis of J-ROCKET AF. J Stroke Cerebrovasc Dis. 2013 Nov;22(8):1317-25. doi: 10.1016/j.jstrokecerebrovasdis.2012.12.010. Epub 2013 Jan 22.
• Hori M, Matsumoto M, Tanahashi N, Momomura S, Uchiyama S, Goto S, Izumi T, Koretsune Y, Kajikawa M, Kato M, Ueda H, Iwamoto K, Tajiri M; J-ROCKET AF study investigators. Safety and efficacy of adjusted dose of rivaroxaban in Japanese patients with non-valvular atrial fibrillation: subanalysis of J-ROCKET AF for patients with moderate renal impairment. Circ J. 2013;77(3):632-8. doi: 10.1253/circj.cj-12-0899. Epub 2012 Dec 8.
• Tanigawa T, Kaneko M, Hashizume K, Kajikawa M, Ueda H, Tajiri M, Paolini JF, Mueck W. Model-based dose selection for phase III rivaroxaban study in Japanese patients with non-valvular atrial fibrillation. Drug Metab Pharmacokinet. 2013;28(1):59-70. doi: 10.2133/dmpk.dmpk-12-rg-034. Epub 2012 Jul 17.
• Kaneko M, Tanigawa T, Hashizume K, Kajikawa M, Tajiri M, Mueck W. Confirmation of model-based dose selection for a Japanese phase III study of rivaroxaban in non-valvular atrial fibrillation patients. Drug Metab Pharmacokinet. 2013;28(4):321-31. doi: 10.2133/dmpk.dmpk-12-rg-109. Epub 2013 Jan 22.
• Matsumoto M, Hori M, Tanahashi N, Momomura S, Uchiyama S, Goto S, Izumi T, Koretsune Y, Kajikawa M, Kato M, Ueda H, Iekushi K, Yamanaka S, Tajiri M; J-ROCKET AF Study Investigators. Rivaroxaban versus warfarin in Japanese patients with non-valvular atrial fibrillation in relation to hypertension: a subgroup analysis of the J-ROCKET AF trial. Hypertens Res. 2014 May;37(5):457-62. doi: 10.1038/hr.2014.1. Epub 2014 Jan 30.
• Uchiyama S, Hori M, Matsumoto M, Tanahashi N, Momomura S, Goto S, Izumi T, Koretsune Y, Kajikawa M, Kato M, Ueda H, Iekushi K, Yamanaka S, Tajiri M; J-ROCKET AF Study Investigators. Net clinical benefit of rivaroxaban versus warfarin in Japanese patients with nonvalvular atrial fibrillation: a subgroup analysis of J-ROCKET AF. J Stroke Cerebrovasc Dis. 2014 May-Jun;23(5):1142-7. doi: 10.1016/j.jstrokecerebrovasdis.2013.10.001. Epub 2013 Nov 1.
• Hori M, Matsumoto M, Tanahashi N, Momomura S, Uchiyama S, Goto S, Izumi T, Koretsune Y, Kajikawa M, Kato M, Ueda H, Iekushi K, Yamanaka S, Tajiri M; J-ROCKET AF Study Investigators. Rivaroxaban versus warfarin in Japanese patients with nonvalvular atrial fibrillation in relation to the CHADS2 score: a subgroup analysis of the J-ROCKET AF trial. J Stroke Cerebrovasc Dis. 2014 Feb;23(2):379-83. doi: 10.1016/j.jstrokecerebrovasdis.2013.07.021. Epub 2013 Aug 15.
• Hori M, Kajikawa M. The J-ROCKET AF Study: a matter of ethnicity or a matter of weight? Reply. Circ J. 2013;77(10):2637. doi: 10.1253/circj.cj-13-0879. Epub 2013 Aug 1. No abstract available.
• Hori M, Matsumoto M, Tanahashi N, Momomura S, Uchiyama S, Goto S, Izumi T, Koretsune Y, Kajikawa M, Kato M, Ueda H, Iekushi K, Yamanaka S, Tajiri M; J-ROCKET AF Study Investigators. Rivaroxaban vs. warfarin in Japanese patients with non-valvular atrial fibrillation in relation to age. Circ J. 2014;78(6):1349-56. doi: 10.1253/circj.cj-13-1324. Epub 2014 Apr 7.

Study record dates

Study Major Dates

• Study Start: June 1, 2007
• Primary Completion (Actual): December 1, 2009
• Study Completion (Actual): January 1, 2010

Study Registration Dates

• First Submitted: June 29, 2007
• First Submitted That Met QC Criteria: June 29, 2007
• First Posted (Estimate): July 2, 2007

Study Record Updates

• Last Update Posted (Estimate): April 20, 2015
• Last Update Submitted That Met QC Criteria: April 1, 2015
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Keywords: Rivaroxaban; BAY59-7939; Non-Valvular Atrial Fibrillation; Japanese Patients; Phase III; 12620
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban; Warfarin
• Other Study ID Numbers: 12620

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No