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

• Sponsor: Bayer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00494871
• Collaborator: Janssen R&D, L.L.C. (Other)
• Enrollment: 1,280
• Locations: 165
• Arms: 2
• Duration (Months): 31
• Patients Per Site: 7.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Atrial Fibrillation	Drug: Rivaroxaban (Xarelto, BAY59-7939); Drug: Warfarin; Drug: Rivaroxaban placebo; Drug: Warfarin placebo	Phase 3

Detailed Description

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 1280 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Prevention
• Official Title: 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
• Study Start Date: Jun 1, 2007
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Jan 1, 2010

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Event Rate of the Composite Endpoint of Adjudicated Major Bleeding or Adjudicated Non-major Clinically Relevant Bleeding [Up to 2 days after the last dose]

   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.

Secondary Outcome Measures

1. Event Rate of the Composite Endpoint of Adjudicated Stroke and Non-central Nervous System (CNS) Systemic Embolism [Up to 2 days after the last dose]

   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.

2. Event Rate of the Composite Endpoint of Adjudicated Stroke, Non-CNS Systemic Embolism, and Vascular Death [Up to 2 days after the last dose]

   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.

3. Event Rate of the Composite Endpoint of Adjudicated Stroke, Non-CNS Systemic Embolism, Myocardial Infarction, and Vascular Death [Up to 2 days after the last dose]

   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.

4. Event Rate of Stroke [Up to 2 days after the last dose]

   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.).

5. Event Rate of Non-CNS Systemic Embolism [Up to 2 days after the last dose]

   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.

6. Event Rate of Myocardial Infarction [Up to 2 days after the last dose]

   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.

7. Event Rate of Vascular Death [Up to 2 days after the last dose]

   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)

8. Event Rate of Stroke With Serious Residual Disability [Up to 2 days after the last dose]

   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.

9. Event Rate of All-cause Death [Up to 2 days after the last dose]

   All events were adjudicated and confirmed by a central independent committee blinded to treatment. All-cause death included vascular death and non-vascular death.

10. Event Rate of Adjudicated Major Bleeding [Up to 2 days after the last dose]

    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.

11. Event Rate Adjudicated Non-major Clinically Relevant Bleeding [Up to 2 days after the last dose]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Kasugai	Aichi	Japan	487-0013
2		Nagoya	Aichi	Japan	453-8511
3		Nagoya	Aichi	Japan	454-8502
4		Nagoya	Aichi	Japan	455-8530
5		Nagoya	Aichi	Japan	457-8510
6		Nagoya	Aichi	Japan	462-0825
7		Okazaki	Aichi	Japan	444-8553
8		Goshogawara	Aomori	Japan	037-0053
9		Hirosaki	Aomori	Japan	036-8082
10		Hirosaki	Aomori	Japan	036-8545
11		Asahi	Chiba	Japan	289-2511
12		Funabashi	Chiba	Japan	274-8503
13		Imba	Chiba	Japan	270-1694
14		Matsudo	Chiba	Japan	270-2251
15		Matsudo	Chiba	Japan	271-0077
16		Yotsukaido	Chiba	Japan	284-0032
17		Imabari	Ehime	Japan	799-1592
18		Matsuyama	Ehime	Japan	790-0024
19		Matsuyama	Ehime	Japan	790-0925
20		Matsuyama	Ehime	Japan	791-8026
21		Niihama	Ehime	Japan	792-8543
22		Saijo	Ehime	Japan	793-0030
23		Toon	Ehime	Japan	791-0281
24		Chikushi-gun	Fukuoka	Japan	811-1244
25		Chikushino	Fukuoka	Japan	818-8502
26		Chikushino	Fukuoka	Japan	818-8516
27		Kasuga	Fukuoka	Japan	816-0833
28		Kasuga	Fukuoka	Japan	816-0864
29		Kitakyushu	Fukuoka	Japan	800-0057
30		Kitakyushu	Fukuoka	Japan	806-8501
31		Kurume	Fukuoka	Japan	830-8577
32		Ogori	Fukuoka	Japan	838-0141
33		Yame	Fukuoka	Japan	834-0004
34		Yame	Fukuoka	Japan	834-0006
35		Koriyama	Fukushima	Japan	963-8052
36		Ogaki	Gifu	Japan	503-8502
37		Maebashi	Gunma	Japan	371-8511
38		Mebashi	Gunma	Japan	371-0014
39		Otake	Hiroshima	Japan	739-0696
40		Asahikawa	Hokkaido	Japan	078-8214
41		Chitose	Hokkaido	Japan	066-0034
42		Hakodate	Hokkaido	Japan	040-8611
43		Muroran	Hokkaido	Japan	051-8501
44		Otaru	Hokkaido	Japan	047-8510
45		Sapporo	Hokkaido	Japan	004-0052
46		Sapporo	Hokkaido	Japan	060-0033
47		Sapporo	Hokkaido	Japan	060-0061
48		Sapporo	Hokkaido	Japan	060-8570
49		Sapporo	Hokkaido	Japan	064-0807
50		Sapporo	Hokkaido	Japan	064-8570
51		Sapporo	Hokkaido	Japan	065-0027
52		Sapporo	Hokkaido	Japan	065-0033
53		Sapporo	Hokkaido	Japan	065-8611
54		Sunagawa	Hokkaido	Japan	073-0196
55		Tomakomai	Hokkaido	Japan	053-8506
56		Kobe	Hyogo	Japan	651-0073
57		Kobe	Hyogo	Japan	651-1145
58		Kobe	Hyogo	Japan	652-0803
59		Higashiibaraki	Ibaraki	Japan	311-3193
60		Hitachi	Ibaraki	Japan	317-0077
61		Joso	Ibaraki	Japan	303-0016
62		Kasama	Ibaraki	Japan	309-1793
63		Moriya	Ibaraki	Japan	302-0112
64		Namegata	Ibaraki	Japan	311-3516
65		Toride	Ibaraki	Japan	302-0022
66		Kanazawa	Ishikawa	Japan	920-8650
67		Nomi	Ishikawa	Japan	923-1100
68		Hanamaki	Iwate	Japan	025-0075
69		Morioka	Iwate	Japan	020-0103
70		Marugame	Kagawa	Japan	763-8502
71		Takamatsu	Kagawa	Japan	760-0018
72		Izumi	Kagoshima	Japan	899-0131
73		Atsugi	Kanagawa	Japan	243-8551
74		Fujisawa	Kanagawa	Japan	251-0041
75		Fujisawa	Kanagawa	Japan	251-8550
76		Kamakura	Kanagawa	Japan	247-8533
77		Kawasaki	Kanagawa	Japan	216-8511
78		Yokohama	Kanagawa	Japan	227-0046
79		Yokohama	Kanagawa	Japan	231-8682
80		Yokohama	Kanagawa	Japan	236-0037
81		Yokohama	Kanagawa	Japan	236-0051
82		Nangoku	Kochi	Japan	783-8509
83		Uji	Kyoto	Japan	611-0042
84		Kuwana	Mie	Japan	511-0068
85		Sendai	Miyagi	Japan	980-0803
86		Sendai	Miyagi	Japan	981-3107
87		Sendai	Miyagi	Japan	983-0821
88		Sendai	Miyagi	Japan	983-8512
89		Sendai	Miyagi	Japan	983-8520
90		Komoro	Nagano	Japan	384-8588
91		Matsumoto	Nagano	Japan	390-8510
92		Suwa	Nagano	Japan	392-8510
93		Joetsu	Niigata	Japan	949-3193
94		Nagaoka	Niigata	Japan	940-8621
95		Beppu	Oita	Japan	874-0011
96		Beppu	Oita	Japan	874-0901
97		Yufu	Oita	Japan	879-5593
98		Kasaoka	Okayama	Japan	714-0043
99		Shimajiri	Okinawa	Japan	901-0493
100		Daito	Osaka	Japan	574-0074
101		Higashiosaka	Osaka	Japan	578-8588
102		Hirakata	Osaka	Japan	573-0153
103		Hirakata	Osaka	Japan	573-8511
104		Kawachinagano	Osaka	Japan	586-8521
105		Kishiwada	Osaka	Japan	596-8522
106		Takatsuki	Osaka	Japan	569-1096
107		Toyonaka	Osaka	Japan	560-0022
108		Yao	Osaka	Japan	581-0011
109		Hanyu	Saitama	Japan	348-8505
110		Kasukage	Saitama	Japan	344-0035
111		Kitamoto	Saitama	Japan	364-8501
112		Tokorozawa	Saitama	Japan	359-1141
113		Tokorozawa	Saitama	Japan	359-1142
114		Wako	Saitama	Japan	351-0102
115		Kusatsu	Shiga	Japan	525-8585
116		Fujinomiya	Shizuoka	Japan	418-0076
117		Fukuroi	Shizuoka	Japan	437-0061
118		Hamamatsu	Shizuoka	Japan	432-8580
119		Hamamatsu	Shizuoka	Japan	433-8558
120		Iwata	Shizuoka	Japan	438-8550
121		Shimada	Shizuoka	Japan	427-8502
122		Naruto	Tokushima	Japan	772-8503
123		Edogawa-ku	Tokyo	Japan	133-0052
124		Hachioji	Tokyo	Japan	192-0045
125		Higashikurume	Tokyo	Japan	203-0033
126		Itabashi-ku	Tokyo	Japan	173-8610
127		Itabashi-ku	Tokyo	Japan	175-0082
128		Meguro-ku	Tokyo	Japan	153-8515
129		Ota-ku	Tokyo	Japan	145-0065
130		Shibuya-ku	Tokyo	Japan	150-0013
131		Shinagawa-ku	Tokyo	Japan	141-0001
132		Shinjuku-ku	Tokyo	Japan	162-8655
133		Higashikawada	Yamagata	Japan	999-7782
134		Shimonoseki	Yamaguchi	Japan	750-0061
135		Shunan	Yamaguchi	Japan	745-8522
136		Fukui		Japan	910-0067
137		Fukuoka		Japan	810-8563
138		Fukuoka		Japan	811-0213
139		Fukuoka		Japan	813-0044
140		Fukuoka		Japan	814-0180
141		Gifu		Japan	500-8225
142		Kagoshima		Japan	891-0116
143		Kumamoto		Japan	860-0008
144		Kyoto		Japan	602-8026
145		Nagasaki		Japan	850-8555
146		Oita		Japan	870-0021
147		Oita		Japan	870-0192
148		Oita		Japan	870-0263
149		Oita		Japan	870-0917
150		Okayama		Japan	700-8558
151		Okayama		Japan	700-8607
152		Okinawa		Japan	904-8585
153		Osaka		Japan	530-0001
154		Osaka		Japan	530-8480
155		Osaka		Japan	537-0011
156		Osaka		Japan	540-0006
157		Osaka		Japan	558-0011
158		Osaka		Japan	558-8558
159		Shizuoka		Japan	421-0193
160		Shizuoka		Japan	422-8527
161		Shizuoka		Japan	424-8636
162		Tokushima		Japan	770-0011
163		Tottori		Japan	689-0203
164		Toyama		Japan	930-0194
165		Wakayama		Japan	640-8505

Sponsors and Collaborators

• Bayer
• Janssen R&D, L.L.C.

Investigators

• Study Director: Bayer Study Director, Bayer

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT00494871
• Other Study ID Numbers: 12620
• First Posted: Jul 2, 2007
• Last Update Posted: Apr 20, 2015
• Last Verified: Apr 1, 2015

• Keywords provided by Bayer: BAY59-7939; Rivaroxaban; Non-Valvular Atrial Fibrillation; Japanese Patients; Phase III; 12620
• Additional relevant MeSH terms: Atrial Fibrillation; Warfarin; Rivaroxaban

Study Results

Participant Flow

Recruitment Details	The first participant entered the study on 08 Jun 2007, and the last participant completed the study on 19 Jan 2010. The study was conducted at 167 centers in Japan. 164 study centers enrolled at least 1 participant.
Pre-assignment Detail	In total, 1439 participants were screened for study eligibility; 159 participants were screening failures and were not randomized. Therefore, 1280 participants (640 in each group) were randomized.

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Warfarin
Arm/Group Description	Participants received once daily (OD) a rivaroxaban 15 mg tablet and a warfarin placebo tablet during the double-blind treatment period	Participants received OD a warfarin potassium tablet and a rivaroxaban placebo tablet during the double-blind treatment period
Period Title: Double-blind (DB) Treatment Period
STARTED	640	640
Started Treatment	639	639
COMPLETED	480	468
NOT COMPLETED	160	172
Period Title: Double-blind (DB) Treatment Period
STARTED	639	639
Entered FU and Valid for Safety	628	630
COMPLETED	610	616
NOT COMPLETED	29	23

Baseline Characteristics

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Warfarin	Total
Arm/Group Description	Participants received once daily (OD) a rivaroxaban 15 mg tablet and a warfarin placebo tablet during the double-blind treatment period	Participants received OD a warfarin potassium tablet and a rivaroxaban placebo tablet during the double-blind treatment period	Total of all reporting groups
Overall Participants	640	640	1280
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	71.0 (8.3)	71.2 (7.9)	71.1 (8.1)
Sex: Female, Male (Count of Participants)
Female	110 17.2%	140 21.9%	250 19.5%
Male	530 82.8%	500 78.1%	1030 80.5%
CL(CR) [creatinine clearance] (Number) [Number]
<50 mL/min	141 22%	143 22.3%	284 22.2%
50 to <80 mL/min	329 51.4%	329 51.4%	658 51.4%
≥80 mL/min	170 26.6%	168 26.3%	338 26.4%

Outcome Measures

1. Primary Outcome

Title	Event Rate of the Composite Endpoint of Adjudicated Major Bleeding or Adjudicated Non-major Clinically Relevant Bleeding
Description	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.
Time Frame	Up to 2 days after the last dose

Outcome Measure Data

Analysis Population Description

The safety analysis population consisted of randomized participants who took at least one dose of study treatment (639 in each treatment group).

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Warfarin
Arm/Group Description	Participants received once daily (OD) a rivaroxaban 15 mg tablet and a warfarin placebo tablet during the double-blind treatment period	Participants received OD a warfarin potassium tablet and a rivaroxaban placebo tablet during the double-blind treatment period
Measure Participants	639	639
Number [Events per 100 patient-years]	18.04	16.42

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban (Xarelto, BAY59-7939), Warfarin
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority margin of 2.0
Statistical Test of Hypothesis	p-Value	0.025
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.11
	Confidence Interval	(2-Sided) 95%; 0.87 to 1.42
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Event Rate of the Composite Endpoint of Adjudicated Stroke and Non-central Nervous System (CNS) Systemic Embolism
Description	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.
Time Frame	Up to 2 days after the last dose

Outcome Measure Data

Analysis Population Description

The per-protocol analysis population consisted of randomized participants excluding those who had specific pre-defined major protocol deviations (637 in each treatment group).

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Warfarin
Arm/Group Description	Participants received once daily (OD) a rivaroxaban 15 mg tablet and a warfarin placebo tablet during the double-blind treatment period	Participants received OD a warfarin potassium tablet and a rivaroxaban placebo tablet during the double-blind treatment period
Measure Participants	637	637
Number [Events per 100 patient-years]	1.26	2.61

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban (Xarelto, BAY59-7939), Warfarin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.49
	Confidence Interval	(2-Sided) 95%; 0.24 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Event Rate of the Composite Endpoint of Adjudicated Stroke, Non-CNS Systemic Embolism, and Vascular Death
Description	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.
Time Frame	Up to 2 days after the last dose

Outcome Measure Data

Analysis Population Description

The per-protocol analysis population consisted of randomized participants excluding those who had specific pre-defined major protocol deviations (637 in each treatment group).

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Warfarin
Arm/Group Description	Participants received once daily (OD) a rivaroxaban 15 mg tablet and a warfarin placebo tablet during the double-blind treatment period	Participants received OD a warfarin potassium tablet and a rivaroxaban placebo tablet during the double-blind treatment period
Measure Participants	637	637
Number [Events per 100 patient-years]	1.83	2.85

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban (Xarelto, BAY59-7939), Warfarin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; 0.34 to 1.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Event Rate of the Composite Endpoint of Adjudicated Stroke, Non-CNS Systemic Embolism, Myocardial Infarction, and Vascular Death
Description	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.
Time Frame	Up to 2 days after the last dose

Outcome Measure Data

Analysis Population Description

The per-protocol analysis population consisted of randomized participants excluding those who had specific pre-defined major protocol deviations (637 in each treatment group).

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Warfarin
Arm/Group Description	Participants received once daily (OD) a rivaroxaban 15 mg tablet and a warfarin placebo tablet during the double-blind treatment period	Participants received OD a warfarin potassium tablet and a rivaroxaban placebo tablet during the double-blind treatment period
Measure Participants	637	637
Number [Events per 100 patient-years]	2.18	2.97

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban (Xarelto, BAY59-7939), Warfarin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95%; 0.41 to 1.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Event Rate of Stroke
Description	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.).
Time Frame	Up to 2 days after the last dose

Outcome Measure Data

Analysis Population Description

The per-protocol analysis population consisted of randomized participants excluding those who had specific pre-defined major protocol deviations (637 in each treatment group).

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Warfarin
Arm/Group Description	Participants received once daily (OD) a rivaroxaban 15 mg tablet and a warfarin placebo tablet during the double-blind treatment period	Participants received OD a warfarin potassium tablet and a rivaroxaban placebo tablet during the double-blind treatment period
Measure Participants	637	637
Number [Events per 100 patient-years]	1.15	2.49

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban (Xarelto, BAY59-7939), Warfarin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.46
	Confidence Interval	(2-Sided) 95%; 0.22 to 0.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Event Rate of Non-CNS Systemic Embolism
Description	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.
Time Frame	Up to 2 days after the last dose

Outcome Measure Data

Analysis Population Description

The per-protocol analysis population consisted of randomized participants excluding those who had specific pre-defined major protocol deviations (637 in each treatment group).

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Warfarin
Arm/Group Description	Participants received once daily (OD) a rivaroxaban 15 mg tablet and a warfarin placebo tablet during the double-blind treatment period	Participants received OD a warfarin potassium tablet and a rivaroxaban placebo tablet during the double-blind treatment period
Measure Participants	637	637
Number [Events per 100 patient-years]	0.11	0.12

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban (Xarelto, BAY59-7939), Warfarin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.06 to 15.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Event Rate of Myocardial Infarction
Description	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.
Time Frame	Up to 2 days after the last dose

Outcome Measure Data

Analysis Population Description

The per-protocol analysis population consisted of randomized participants excluding those who had specific pre-defined major protocol deviations (637 in each treatment group).

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Warfarin
Arm/Group Description	Participants received once daily (OD) a rivaroxaban 15 mg tablet and a warfarin placebo tablet during the double-blind treatment period	Participants received OD a warfarin potassium tablet and a rivaroxaban placebo tablet during the double-blind treatment period
Measure Participants	637	637
Number [Events per 100 patient-years]	0.34	0.12

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban (Xarelto, BAY59-7939), Warfarin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.93
	Confidence Interval	(2-Sided) 95%; 0.30 to 28.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Event Rate of Vascular Death
Description	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)
Time Frame	Up to 2 days after the last dose

Outcome Measure Data

Analysis Population Description

The per-protocol analysis population consisted of randomized participants excluding those who had specific pre-defined major protocol deviations (637 in each treatment group).

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Warfarin
Arm/Group Description	Participants received once daily (OD) a rivaroxaban 15 mg tablet and a warfarin placebo tablet during the double-blind treatment period	Participants received OD a warfarin potassium tablet and a rivaroxaban placebo tablet during the double-blind treatment period
Measure Participants	637	637
Number [Events per 100 patient-years]	0.69	0.24

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban (Xarelto, BAY59-7939), Warfarin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.97
	Confidence Interval	(2-Sided) 95%; 0.60 to 14.70
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Event Rate of Stroke With Serious Residual Disability
Description	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.
Time Frame	Up to 2 days after the last dose

Outcome Measure Data

Analysis Population Description

The per-protocol analysis population consisted of randomized participants excluding those who had specific pre-defined major protocol deviations (637 in each treatment group).

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Warfarin
Arm/Group Description	Participants received once daily (OD) a rivaroxaban 15 mg tablet and a warfarin placebo tablet during the double-blind treatment period	Participants received OD a warfarin potassium tablet and a rivaroxaban placebo tablet during the double-blind treatment period
Measure Participants	637	637
Number [Events per 100 patient-years]	0.57	1.19

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban (Xarelto, BAY59-7939), Warfarin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.48
	Confidence Interval	(2-Sided) 95%; 0.16 to 1.40
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Event Rate of All-cause Death
Description	All events were adjudicated and confirmed by a central independent committee blinded to treatment. All-cause death included vascular death and non-vascular death.
Time Frame	Up to 2 days after the last dose

Outcome Measure Data

Analysis Population Description

The per-protocol analysis population consisted of randomized participants excluding those who had specific pre-defined major protocol deviations (637 in each treatment group).

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Warfarin
Arm/Group Description	Participants received once daily (OD) a rivaroxaban 15 mg tablet and a warfarin placebo tablet during the double-blind treatment period	Participants received OD a warfarin potassium tablet and a rivaroxaban placebo tablet during the double-blind treatment period
Measure Participants	637	637
Number [Events per 100 patient-years]	0.80	0.59

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban (Xarelto, BAY59-7939), Warfarin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.37
	Confidence Interval	(2-Sided) 95%; 0.43 to 4.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Event Rate of Adjudicated Major Bleeding
Description	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.
Time Frame	Up to 2 days after the last dose

Outcome Measure Data

Analysis Population Description

The safety analysis population consisted of randomized participants who took at least one dose of study treatment (639 in each treatment group).

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Warfarin
Arm/Group Description	Participants received once daily (OD) a rivaroxaban 15 mg tablet and a warfarin placebo tablet during the double-blind treatment period	Participants received OD a warfarin potassium tablet and a rivaroxaban placebo tablet during the double-blind treatment period
Measure Participants	639	639
Number [Events per 100 patient-years]	3.00	3.59

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban (Xarelto, BAY59-7939), Warfarin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.50 to 1.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Event Rate Adjudicated Non-major Clinically Relevant Bleeding
Description	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.
Time Frame	Up to 2 days after the last dose

Outcome Measure Data

Analysis Population Description

The safety analysis population consisted of randomized participants who took at least one dose of study treatment (639 in each treatment group).

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Warfarin
Arm/Group Description	Participants received once daily (OD) a rivaroxaban 15 mg tablet and a warfarin placebo tablet during the double-blind treatment period	Participants received OD a warfarin potassium tablet and a rivaroxaban placebo tablet during the double-blind treatment period
Measure Participants	639	639
Number [Events per 100 patient-years]	15.42	12.99

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban (Xarelto, BAY59-7939), Warfarin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.20
	Confidence Interval	(2-Sided) 95%; 0.92 to 1.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Reporting Group (RG) 1 + 2: Safety data collected start with the first dose of study drug up to 2 days after the last dose; Reporting Group (RG) 3 + 4: Safety data collected from last dose plus 2 days to end of trial.
Adverse Event Reporting Description	RG3: During follow-up period, participants could be transitioned from study drug to an open-label warfarin or other appropriate therapy.
Arm/Group Title	RG1: Rivaroxaban Double-blind (DB) Period		RG2: Warfarin DB Period		RG3: Rivaroxaban Follow-up (FU) Period		RG4: Warfarin FU Period
Arm/Group Description	Participants orally administered a rivaroxaban 15 mg tablet (a 10 mg tablet for participants with creatinine clearance of 30 to 49 mL/min, inclusive, at screening) and a warfarin placebo tablet once daily (OD) during the double-blind treatment period. Safety data collected start with the first dose of study drug up to 2 days after the last dose		Participants orally administered a warfarin potassium tablet and a rivaroxaban placebo tablet OD during the double-blind treatment period. Safety data collected start with the first dose of study drug up to 2 days after the last dose		Participants orally administered a rivaroxaban 15 mg tablet (a 10 mg tablet for participants with creatinine clearance of 30 to 49 mL/min, inclusive, at screening) and a warfarin placebo tablet once daily (OD) during the double-blind treatment period. Safety data collected from last dose plus 2 days to end of trial		Participants orally administered a warfarin potassium tablet and a rivaroxaban placebo tablet OD during the double-blind treatment period. Safety data collected from last dose plus 2 days to end of trial
All Cause Mortality
	RG1: Rivaroxaban Double-blind (DB) Period		RG2: Warfarin DB Period		RG3: Rivaroxaban Follow-up (FU) Period		RG4: Warfarin FU Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	RG1: Rivaroxaban Double-blind (DB) Period		RG2: Warfarin DB Period		RG3: Rivaroxaban Follow-up (FU) Period		RG4: Warfarin FU Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	151/639 (23.6%)		155/639 (24.3%)		50/628 (8%)		37/630 (5.9%)
Blood and lymphatic system disorders
Anaemia	1/639 (0.2%)	1	3/639 (0.5%)	3	2/628 (0.3%)	2	0/630 (0%)	0
Disseminated intravascular coagulation	0/639 (0%)	0	0/639 (0%)	0	2/628 (0.3%)	2	0/630 (0%)	0
Hypoprothrombinaemia	0/639 (0%)	0	0/639 (0%)	0	2/628 (0.3%)	2	0/630 (0%)	0
Iron deficiency anaemia	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Thrombocytopenia	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Cardiac disorders
Acute myocardial infarction	2/639 (0.3%)	2	1/639 (0.2%)	1	0/628 (0%)	0	1/630 (0.2%)	1
Angina pectoris	1/639 (0.2%)	1	2/639 (0.3%)	3	0/628 (0%)	0	0/630 (0%)	0
Angina unstable	2/639 (0.3%)	2	0/639 (0%)	0	2/628 (0.3%)	2	1/630 (0.2%)	1
Aortic valve incompetence	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	1/630 (0.2%)	1
Atrial fibrillation	4/639 (0.6%)	5	2/639 (0.3%)	2	0/628 (0%)	0	1/630 (0.2%)	1
Atrial flutter	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	1/630 (0.2%)	1
Atrioventricular block complete	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Bradycardia	0/639 (0%)	0	1/639 (0.2%)	1	1/628 (0.2%)	1	0/630 (0%)	0
Cardiac arrest	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	1/630 (0.2%)	1
Cardiac failure	12/639 (1.9%)	12	11/639 (1.7%)	18	3/628 (0.5%)	3	4/630 (0.6%)	4
Cardiac failure acute	0/639 (0%)	0	1/639 (0.2%)	3	0/628 (0%)	0	0/630 (0%)	0
Cardiac failure chronic	3/639 (0.5%)	3	3/639 (0.5%)	3	0/628 (0%)	0	0/630 (0%)	0
Cardiac failure congestive	2/639 (0.3%)	2	3/639 (0.5%)	3	1/628 (0.2%)	1	1/630 (0.2%)	1
Cardio-respiratory arrest	0/639 (0%)	0	2/639 (0.3%)	2	1/628 (0.2%)	1	0/630 (0%)	0
Cor pulmonale	0/639 (0%)	0	0/639 (0%)	0	1/628 (0.2%)	1	0/630 (0%)	0
Mitral valve incompetence	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	2/630 (0.3%)	2
Myocardial ischaemia	0/639 (0%)	0	0/639 (0%)	0	1/628 (0.2%)	1	0/630 (0%)	0
Sick sinus syndrome	0/639 (0%)	0	2/639 (0.3%)	2	0/628 (0%)	0	0/630 (0%)	0
Ventricular tachycardia	2/639 (0.3%)	2	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Ear and labyrinth disorders
Vertigo	1/639 (0.2%)	1	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Auditory meatus external erosion	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Sudden hearing loss	1/639 (0.2%)	1	2/639 (0.3%)	2	0/628 (0%)	0	0/630 (0%)	0
Eye disorders
Cataract	9/639 (1.4%)	10	7/639 (1.1%)	8	0/628 (0%)	0	0/630 (0%)	0
Glaucoma	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Macular degeneration	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Retinal detachment	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Retinal haemorrhage	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Macular hole	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Anal polyp	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Colonic polyp	5/639 (0.8%)	5	9/639 (1.4%)	12	0/628 (0%)	0	1/630 (0.2%)	1
Dental caries	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Diarrhoea	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Diverticulum intestinal haemorrhagic	0/639 (0%)	0	3/639 (0.5%)	3	0/628 (0%)	0	0/630 (0%)	0
Duodenal ulcer haemorrhage	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Enterocolitis	1/639 (0.2%)	1	2/639 (0.3%)	2	0/628 (0%)	0	0/630 (0%)	0
Gastric ulcer	2/639 (0.3%)	2	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Gastric ulcer haemorrhage	3/639 (0.5%)	3	2/639 (0.3%)	2	0/628 (0%)	0	0/630 (0%)	0
Gastrointestinal haemorrhage	0/639 (0%)	0	4/639 (0.6%)	4	0/628 (0%)	0	0/630 (0%)	0
Gingival bleeding	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Haemorrhoids	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Ileus	0/639 (0%)	0	4/639 (0.6%)	4	0/628 (0%)	0	0/630 (0%)	0
Inguinal hernia	1/639 (0.2%)	1	2/639 (0.3%)	2	0/628 (0%)	0	1/630 (0.2%)	1
Intestinal obstruction	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Large intestine perforation	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Mallory-Weiss syndrome	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Melaena	1/639 (0.2%)	1	1/639 (0.2%)	2	1/628 (0.2%)	1	0/630 (0%)	0
Mouth haemorrhage	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Nausea	1/639 (0.2%)	1	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Pancreatitis acute	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Periodontal disease	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Periodontitis	1/639 (0.2%)	1	3/639 (0.5%)	4	0/628 (0%)	0	0/630 (0%)	0
Peritonitis	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Rectal polyp	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Tooth loss	0/639 (0%)	0	0/639 (0%)	0	0/628 (0%)	0	1/630 (0.2%)	1
Upper gastrointestinal haemorrhage	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Vomiting	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Subileus	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Mechanical ileus	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
General disorders
Malaise	0/639 (0%)	0	2/639 (0.3%)	2	0/628 (0%)	0	0/630 (0%)	0
Oedema	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Oedema peripheral	0/639 (0%)	0	0/639 (0%)	0	0/628 (0%)	0	1/630 (0.2%)	1
Pyrexia	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	1/630 (0.2%)	1
Sudden death	4/639 (0.6%)	4	2/639 (0.3%)	2	3/628 (0.5%)	3	0/630 (0%)	0
Sudden cardiac death	1/639 (0.2%)	1	0/639 (0%)	0	1/628 (0.2%)	1	0/630 (0%)	0
Catheter site haemorrhage	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Hepatobiliary disorders
Bile duct stone	0/639 (0%)	0	2/639 (0.3%)	2	0/628 (0%)	0	0/630 (0%)	0
Cholangitis acute	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Cholecystitis	0/639 (0%)	0	0/639 (0%)	0	0/628 (0%)	0	1/630 (0.2%)	1
Cholecystitis acute	0/639 (0%)	0	1/639 (0.2%)	1	1/628 (0.2%)	1	1/630 (0.2%)	1
Cholelithiasis	0/639 (0%)	0	0/639 (0%)	0	0/628 (0%)	0	1/630 (0.2%)	1
Hepatic function abnormal	2/639 (0.3%)	2	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Liver disorder	0/639 (0%)	0	0/639 (0%)	0	1/628 (0.2%)	1	0/630 (0%)	0
Immune system disorders
Anaphylactic reaction	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Infections and infestations
Appendicitis	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Bronchitis	1/639 (0.2%)	1	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Bronchopneumonia	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Cellulitis	2/639 (0.3%)	2	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Diverticulitis	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Gastroenteritis	3/639 (0.5%)	3	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Gastroenteritis viral	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Herpes zoster	1/639 (0.2%)	1	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Liver abscess	0/639 (0%)	0	0/639 (0%)	0	1/628 (0.2%)	1	0/630 (0%)	0
Meningitis bacterial	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Otitis media	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Pneumonia	14/639 (2.2%)	15	10/639 (1.6%)	11	3/628 (0.5%)	3	3/630 (0.5%)	3
Pyelonephritis	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Sepsis	0/639 (0%)	0	2/639 (0.3%)	2	2/628 (0.3%)	2	1/630 (0.2%)	1
Subcutaneous abscess	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Urinary tract infection	2/639 (0.3%)	2	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Anal abscess	1/639 (0.2%)	1	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Lung infection	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Enterocolitis viral	1/639 (0.2%)	1	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Infective spondylitis	0/639 (0%)	0	1/639 (0.2%)	1	1/628 (0.2%)	1	0/630 (0%)	0
Injury, poisoning and procedural complications
Accident	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Accidental exposure	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Femur fracture	2/639 (0.3%)	2	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Fibula fracture	0/639 (0%)	0	2/639 (0.3%)	2	0/628 (0%)	0	0/630 (0%)	0
Patella fracture	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Radius fracture	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Rib fracture	1/639 (0.2%)	1	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Road traffic accident	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Spinal compression fracture	4/639 (0.6%)	6	2/639 (0.3%)	2	0/628 (0%)	0	0/630 (0%)	0
Spinal cord injury	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Spinal cord injury cervical	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Subdural haematoma	1/639 (0.2%)	1	0/639 (0%)	0	1/628 (0.2%)	1	0/630 (0%)	0
Tendon rupture	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Therapeutic agent toxicity	1/639 (0.2%)	1	2/639 (0.3%)	2	0/628 (0%)	0	0/630 (0%)	0
Tibia fracture	0/639 (0%)	0	2/639 (0.3%)	2	0/628 (0%)	0	0/630 (0%)	0
Ulna fracture	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Muscle strain	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Contusion	2/639 (0.3%)	2	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Post procedural haemorrhage	1/639 (0.2%)	1	1/639 (0.2%)	1	0/628 (0%)	0	1/630 (0.2%)	1
Brain contusion	1/639 (0.2%)	1	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Thermal burn	0/639 (0%)	0	0/639 (0%)	0	0/628 (0%)	0	1/630 (0.2%)	1
Coronary artery restenosis	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Skin laceration	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Ligament injury	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Skull fracture	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Investigations
Blood pressure decreased	2/639 (0.3%)	2	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Haemoglobin decreased	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
International normalised ratio increased	0/639 (0%)	0	0/639 (0%)	0	3/628 (0.5%)	3	0/630 (0%)	0
Metabolism and nutrition disorders
Dehydration	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Diabetes mellitus	4/639 (0.6%)	6	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Hyperkalaemia	0/639 (0%)	0	0/639 (0%)	0	0/628 (0%)	0	1/630 (0.2%)	1
Hyponatraemia	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Hypoproteinaemia	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Decreased appetite	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Bursitis	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Chondrocalcinosis pyrophosphate	1/639 (0.2%)	1	1/639 (0.2%)	1	1/628 (0.2%)	1	0/630 (0%)	0
Compartment syndrome	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Haemarthrosis	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Joint effusion	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Lumbar spinal stenosis	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Muscle haemorrhage	1/639 (0.2%)	1	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Neck pain	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Pain in extremity	1/639 (0.2%)	2	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Periarthritis	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Polymyalgia rheumatica	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Rhabdomyolysis	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Spinal osteoarthritis	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Intervertebral disc protrusion	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer	0/639 (0%)	0	2/639 (0.3%)	2	0/628 (0%)	0	0/630 (0%)	0
Bladder neoplasm	0/639 (0%)	0	0/639 (0%)	0	0/628 (0%)	0	1/630 (0.2%)	1
Colon cancer	0/639 (0%)	0	1/639 (0.2%)	1	1/628 (0.2%)	1	1/630 (0.2%)	1
Gastric cancer	2/639 (0.3%)	2	4/639 (0.6%)	4	2/628 (0.3%)	2	2/630 (0.3%)	2
Lipoma	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Lymphoma	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Malignant ascites	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Malignant pleural effusion	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Metastases to liver	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Metastases to lung	0/639 (0%)	0	2/639 (0.3%)	2	0/628 (0%)	0	0/630 (0%)	0
Metastases to lymph nodes	0/639 (0%)	0	0/639 (0%)	0	1/628 (0.2%)	1	0/630 (0%)	0
Metastases to neck	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Nasal sinus cancer	0/639 (0%)	0	0/639 (0%)	0	0/628 (0%)	0	1/630 (0.2%)	1
Oesophageal carcinoma	1/639 (0.2%)	1	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Rectal cancer	1/639 (0.2%)	1	1/639 (0.2%)	1	2/628 (0.3%)	2	0/630 (0%)	0
Small cell lung cancer stage unspecified	2/639 (0.3%)	2	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Uterine cancer	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Tumour haemorrhage	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Lung neoplasm malignant	0/639 (0%)	0	1/639 (0.2%)	1	1/628 (0.2%)	1	0/630 (0%)	0
Large intestine carcinoma	2/639 (0.3%)	2	1/639 (0.2%)	1	1/628 (0.2%)	1	1/630 (0.2%)	1
Prostate cancer	3/639 (0.5%)	3	0/639 (0%)	0	1/628 (0.2%)	1	1/630 (0.2%)	1
Nervous system disorders
Brain stem haemorrhage	0/639 (0%)	0	2/639 (0.3%)	2	0/628 (0%)	0	0/630 (0%)	0
Carotid artery stenosis	1/639 (0.2%)	1	0/639 (0%)	0	1/628 (0.2%)	1	0/630 (0%)	0
Cerebral haemorrhage	1/639 (0.2%)	1	1/639 (0.2%)	1	1/628 (0.2%)	1	0/630 (0%)	0
Cholinergic syndrome	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Convulsion	0/639 (0%)	0	3/639 (0.5%)	4	1/628 (0.2%)	1	0/630 (0%)	0
Dizziness	1/639 (0.2%)	1	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Epilepsy	4/639 (0.6%)	5	1/639 (0.2%)	1	1/628 (0.2%)	1	0/630 (0%)	0
Facial palsy	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Haemorrhage intracranial	0/639 (0%)	0	0/639 (0%)	0	1/628 (0.2%)	1	0/630 (0%)	0
Haemorrhagic cerebral infarction	0/639 (0%)	0	0/639 (0%)	0	2/628 (0.3%)	2	1/630 (0.2%)	1
Hemiplegia	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Hypertensive encephalopathy	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Loss of consciousness	0/639 (0%)	0	1/639 (0.2%)	1	1/628 (0.2%)	1	0/630 (0%)	0
Subarachnoid haemorrhage	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Syncope	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Transient ischaemic attack	2/639 (0.3%)	2	2/639 (0.3%)	2	1/628 (0.2%)	1	2/630 (0.3%)	2
Vertebral artery stenosis	0/639 (0%)	0	0/639 (0%)	0	0/628 (0%)	0	1/630 (0.2%)	1
Carotid artery occlusion	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Thalamus haemorrhage	1/639 (0.2%)	1	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Putamen haemorrhage	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Ischaemic stroke	9/639 (1.4%)	9	18/639 (2.8%)	18	10/628 (1.6%)	12	4/630 (0.6%)	4
Postresuscitation encephalopathy	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Psychiatric disorders
Psychosomatic disease	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Renal and urinary disorders
Acute prerenal failure	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Haematuria	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Nephrolithiasis	1/639 (0.2%)	2	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Renal artery stenosis	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Renal failure	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Renal failure acute	1/639 (0.2%)	1	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Renal impairment	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Renal embolism	1/639 (0.2%)	1	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Reproductive system and breast disorders
Prostatitis	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Asthma	3/639 (0.5%)	3	1/639 (0.2%)	5	0/628 (0%)	0	0/630 (0%)	0
Epistaxis	2/639 (0.3%)	2	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Haemoptysis	0/639 (0%)	0	0/639 (0%)	0	1/628 (0.2%)	1	0/630 (0%)	0
Haemothorax	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Interstitial lung disease	2/639 (0.3%)	2	3/639 (0.5%)	3	0/628 (0%)	0	1/630 (0.2%)	1
Pleural effusion	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Pleurisy	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Pneumonia aspiration	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Pneumothorax	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Pulmonary oedema	0/639 (0%)	0	0/639 (0%)	0	0/628 (0%)	0	1/630 (0.2%)	1
Status asthmaticus	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Upper respiratory tract inflammation	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Bronchial haemorrhage	0/639 (0%)	0	0/639 (0%)	0	1/628 (0.2%)	1	0/630 (0%)	0
Skin and subcutaneous tissue disorders
Eczema	0/639 (0%)	0	0/639 (0%)	0	1/628 (0.2%)	1	0/630 (0%)	0
Haemorrhage subcutaneous	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Rash	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Vascular disorders
Aortic aneurysm	1/639 (0.2%)	1	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Aortic dissection	2/639 (0.3%)	2	0/639 (0%)	0	0/628 (0%)	0	0/630 (0%)	0
Haematoma	0/639 (0%)	0	0/639 (0%)	0	0/628 (0%)	0	1/630 (0.2%)	1
Shock haemorrhagic	1/639 (0.2%)	1	0/639 (0%)	0	1/628 (0.2%)	1	0/630 (0%)	0
Peripheral embolism	0/639 (0%)	0	1/639 (0.2%)	1	0/628 (0%)	0	0/630 (0%)	0
Arteriosclerosis obliterans	0/639 (0%)	0	2/639 (0.3%)	2	0/628 (0%)	0	0/630 (0%)	0
Other (Not Including Serious) Adverse Events
	RG1: Rivaroxaban Double-blind (DB) Period		RG2: Warfarin DB Period		RG3: Rivaroxaban Follow-up (FU) Period		RG4: Warfarin FU Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	474/639 (74.2%)		470/639 (73.6%)		73/628 (11.6%)		61/630 (9.7%)
Cardiac disorders
Cardiac failure	36/639 (5.6%)	39	29/639 (4.5%)	35	5/628 (0.8%)	6	2/630 (0.3%)	2
Eye disorders
Conjunctival haemorrhage	26/639 (4.1%)	32	42/639 (6.6%)	57	9/628 (1.4%)	9	1/630 (0.2%)	1
Gastrointestinal disorders
Constipation	38/639 (5.9%)	46	32/639 (5%)	40	12/628 (1.9%)	12	8/630 (1.3%)	8
Dental caries	28/639 (4.4%)	32	34/639 (5.3%)	35	1/628 (0.2%)	1	0/630 (0%)	0
Diarrhoea	57/639 (8.9%)	71	40/639 (6.3%)	47	3/628 (0.5%)	3	6/630 (1%)	6
Gingival bleeding	54/639 (8.5%)	72	31/639 (4.9%)	38	1/628 (0.2%)	1	2/630 (0.3%)	2
Infections and infestations
Nasopharyngitis	206/639 (32.2%)	378	232/639 (36.3%)	412	16/628 (2.5%)	16	15/630 (2.4%)	16
Injury, poisoning and procedural complications
Contusion	58/639 (9.1%)	82	56/639 (8.8%)	80	4/628 (0.6%)	4	4/630 (0.6%)	4
Wound haemorrhage	33/639 (5.2%)	38	27/639 (4.2%)	31	1/628 (0.2%)	1	1/630 (0.2%)	1
Metabolism and nutrition disorders
Diabetes mellitus	43/639 (6.7%)	48	31/639 (4.9%)	34	0/628 (0%)	0	1/630 (0.2%)	1
Musculoskeletal and connective tissue disorders
Back pain	50/639 (7.8%)	57	56/639 (8.8%)	60	5/628 (0.8%)	5	7/630 (1.1%)	7
Nervous system disorders
Headache	24/639 (3.8%)	29	39/639 (6.1%)	43	6/628 (1%)	6	2/630 (0.3%)	3
Respiratory, thoracic and mediastinal disorders
Epistaxis	102/639 (16%)	203	59/639 (9.2%)	86	6/628 (1%)	8	8/630 (1.3%)	8
Upper respiratory tract inflammation	55/639 (8.6%)	76	74/639 (11.6%)	102	3/628 (0.5%)	3	1/630 (0.2%)	1
Skin and subcutaneous tissue disorders
Eczema	37/639 (5.8%)	50	43/639 (6.7%)	49	2/628 (0.3%)	2	1/630 (0.2%)	1
Haemorrhage subcutaneous	67/639 (10.5%)	147	79/639 (12.4%)	175	9/628 (1.4%)	9	6/630 (1%)	7
Vascular disorders
Hypertension	24/639 (3.8%)	25	32/639 (5%)	36	3/628 (0.5%)	3	2/630 (0.3%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.