Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep Vein Thrombosis - The EINSTEIN DVT Study

• Sponsor: Bayer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00440193
• Collaborator: Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (Industry)
• Enrollment: 3,449
• Locations: 324
• Arms: 2
• Duration (Months): 37
• Patients Per Site: 10.6
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This is a multicenter, randomized, open-label, assessor-blind, event-driven, non-inferiority program for efficacy with a study treatment duration of 3, 6 or 12 months in patients with confirmed acute symptomatic DVT without symptomatic PE (Einstein-DVT).

Condition or Disease	Intervention/Treatment	Phase
Venous Thrombosis	Drug: Rivaroxaban (Xarelto, BAY59-7939); Drug: Enoxaparin followed by VKA	Phase 3

Detailed Description

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

The treatment period was followed by an observational period of 30 days starting the day after the last intake of study medication, regardless of the actual duration of study drug administration. Participants who did not complete the treatment period also entered the observational period. It was also possible that participants did not enter the observational period, e.g. due to withdrawal of consent or termination of study participation. Participants who were transferring from study 11702 DVT (NCT00440193) to the extension study 11899 (NCT00439725) did not enter the observational period.

Study Design

• Study Type: Interventional
• Actual Enrollment: 3449 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep-Vein Thrombosis or Pulmonary Embolism
• Study Start Date: Mar 1, 2007
• Actual Primary Completion Date: Apr 1, 2010
• Actual Study Completion Date: Apr 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rivaroxaban (Xarelto, BAY59-7939) Participants were to receive rivaroxaban 15 mg oral tablet twice daily for 3 weeks, followed by 20 mg once daily	Drug: Rivaroxaban (Xarelto, BAY59-7939); During the first 3 weeks patients will receive 15 mg rivaroxaban twice-daily. Thereafter, patients will receive rivaroxaban 20 mg once-daily. Rivaroxaban will be administered orally and should be taken with food.
Active Comparator: Enoxaparin/VKA Participants were to receive 1.0 mg/kg enoxaparin twice daily (subcutaneous) for at least 5 days, plus vitamin K antagonist (VKA) (oral) at individually titrated doses to achieve a target international normalized ratio (INR) of 2.5 (range: 2.0 to 3.0)	Drug: Enoxaparin followed by VKA; Enoxaparin 1.0 mg/kg twice daily with a minimal duration of 5 days. This 5 days treatment could include the period up to 36 h before randomization if enoxaparin twice-daily was used. VKA should be started as soon as possible but not later than 48 hours after randomization.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Symptomatic Recurrent Venous Thromboembolism [VTE] (i.e. the Composite of Recurrent Deep Vein Thrombosis [DVT] or Fatal or Non-fatal Pulmonary Embolism [PE]) Until the Intended End of Study Treatment [3-, 6- or 12-month study treatment period]

   All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound (for DVT), venography (for DVT), spiral computed tomography (CT) scanning (for PE), pulmonary angiography (for PE), ventilation/perfusion lung scan (for PE), lung scintigraphy (for PE), autopsy (for fatal PE) or unexplained death for which DVT/PE could not be ruled out (for fatal PE), and/or case summaries.

Secondary Outcome Measures

1. Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality Until the Intended End of Study Treatment [3-, 6- or 12-month study treatment period]

   All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound (for DVT), venography (for DVT), spiral computed tomography (CT) scanning (for PE), pulmonary angiography (for PE), ventilation/perfusion lung scan (for PE), lung scintigraphy (for PE), autopsy (for deaths), results/films/images of confirmatory testing, and/or case summaries.

2. Percentage of Participants With an Event for Net Clinical Benefit 1 Until the Intended End of Study Treatment [3-, 6- or 12-month study treatment period]

   Net clinical benefit 1: composite of recurrent DVT or non-fatal or fatal PE, and major bleeding. Major bleeding was overt bleeding associated with 2 g/dL or greater fall in hemoglobin, leading to a transfusion of ≥2 units, occurring in a critical site or contributing to death. Net clinical benefit was considered greater in those participants with fewer composite events. All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment, based on either compression ultrasound, venography, spiral computed tomography scanning, pulmonary angiography, ventilation/perfusion lung scan, lung scintigraphy, autopsy or unexplained death for which DVT/PE could not be ruled out, results/films/images of confirmatory testing, and/or case summaries.

3. Percentage of Participants With Recurrent DVT Until the Intended End of Study Treatment [3-, 6- or 12-month study treatment period]

   All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound, venography, results/films/images of confirmatory testing, and/or case summaries.

4. Percentage of Participants With Clinically Relevant Bleeding, Treatment-emergent (Time Window: Until 2 Days After Last Dose) [3-, 6- or 12-month study treatment period]

   All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Clinically relevant bleeding included major bleeding (overt bleeding associated with 2 g/dL or greater fall in hemoglobin, 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) and non-major bleeding associated with medical intervention, unscheduled physician contact, (temporary) cessation of study treatment, discomfort for the participants such as pain, or impairment of activities of daily life.

5. Percentage of Participants With All Deaths [3-, 6- or 12-month study treatment period]

   All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either autopsy, results/films/images of confirmatory testing, and/or case summaries.

6. Percentage of Participants With Other Vascular Events, On-treatment (Time Window: Until 1 Day After Last Dose) [3-, 6- or 12-month study treatment period]

   All pre-defined vascular events (ST segment elevation myocardial infarction, non ST segment elevation myocardial infarction, unstable angina, ischemic stroke, transient ischemic attack, non-central nervous system systemic embolism or vascular death) were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based results/films/images of confirmatory testing, and/or case summaries.

Other Outcome Measures

1. Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment [3-, 6- or 12-month study treatment period]

   All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment, based on either compression ultrasound, venography, spiral computed tomography scanning, pulmonary angiography, ventilation/perfusion lung scan, lung scintigraphy, autopsy or unexplained death for which DVT/PE could not be ruled out, results/films/images of confirmatory testing, and/or case summaries. Major bleeding was overt bleeding associated with 2 g/dL or greater fall in hemoglobin, leading to a transfusion of ≥2 units, occurring in a critical site or contributing to death.

2. Percentage of Participants With Symptomatic Recurrent Venous Thromboembolism [VTE] (i.e. the Composite of Recurrent Deep Vein Thrombosis [DVT] or Fatal or Non-fatal Pulmonary Embolism [PE]) During Observational Period [Up to 30 days after the last intake of study medication]

   All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound (for DVT), venography (for DVT), spiral computed tomography (CT) scanning (for PE), pulmonary angiography (for PE), ventilation/perfusion lung scan (for PE), lung scintigraphy (for PE), autopsy (for fatal PE) or unexplained death for which DVT/PE could not be ruled out (for fatal PE), results/films/images of confirmatory testing, and/or case summaries.

3. Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality During Observational Period [Up to 30 days after the last intake of study medication]

   All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound (for DVT), venography (for DVT), spiral computed tomography (CT) scanning (for PE), pulmonary angiography (for PE), ventilation/perfusion lung scan (for PE), lung scintigraphy (for PE), autopsy (for deaths), results/films/images of confirmatory testing, and/or case summaries.

4. Percentage of Participants With an Event for Net Clinical Benefit 1 During Observational Period [Up to 30 days after the last intake of study medication]

   Net clinical benefit 1: composite of recurrent DVT or non-fatal or fatal PE or major bleeding. Major bleeding was overt bleeding associated with 2 g/dL or greater fall in hemoglobin, leading to a transfusion of ≥2 units, occurring in a critical site or contributing to death. Net clinical benefit was considered greater in those participants with fewer composite events. All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment, based on either compression ultrasound, venography, spiral computed tomography scanning, pulmonary angiography, ventilation/perfusion lung scan, lung scintigraphy, autopsy or unexplained death for which DVT/PE could not be ruled out, results/films/images of confirmatory testing, and/or case summaries.

5. Percentage of Participants With Recurrent DVT During Observational Period [Up to 30 days after the last intake of study medication]

   All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound, venography, results/films/images of confirmatory testing, and/or case summaries.

6. Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period [Up to 30 days after the last intake of study medication]

   All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment, based on either compression ultrasound, venography, spiral computed tomography scanning, pulmonary angiography, ventilation/perfusion lung scan, lung scintigraphy, autopsy or unexplained death for which DVT/PE could not be ruled out, results/films/images of confirmatory testing, and/or case summaries. Major bleeding was overt bleeding associated with 2 g/dL or greater fall in hemoglobin, leading to a transfusion of ≥2 units, occurring in a critical site or contributing to death.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Confirmed acute symptomatic proximal DVT without symptomatic PE

Exclusion Criteria:

• Legal lower age limitations (country specific)

• Thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat the current episode of DVT and/or PE

• Other indication for VKA than DVT and/or PE

• The pre-randomization anti-coagulant treatment (Criteria # 4) has been prolonged from 36 hours to a maximum of 48 hours.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Little Rock	Arkansas	United States	72205
2		Redlands	California	United States	92373
3		Bay Pines	Florida	United States	33744
4		Miami	Florida	United States	33136-1096
5		Miami	Florida	United States	33136
6		Idaho Falls	Idaho	United States	83404
7		Covington	Louisiana	United States	70433
8		Baltimore	Maryland	United States	21215
9		Boston	Massachusetts	United States	02215
10		Albuquerque	New Mexico	United States	87108-4763
11		Chapel Hill	North Carolina	United States	27599-7035
12		Greensboro	North Carolina	United States	27401
13		Greensboro	North Carolina	United States	27403
14		Oklahoma City	Oklahoma	United States	73104
15		Camp Hill	Pennsylvania	United States	17011
16		Pittsburgh	Pennsylvania	United States	15224
17		Corsicana	Texas	United States	75110
18		San Antonio	Texas	United States	78229
19		Murray	Utah	United States	84157
20		Salt Lake City	Utah	United States	84132
21		Fredericksburg	Virginia	United States	22401
22		Spokane	Washington	United States	99204
23		Tacoma	Washington	United States	98405
24		Garran	Australian Capital Territory	Australia	2605
25		Darlinghurst	New South Wales	Australia	2010
26		Gosford	New South Wales	Australia	2250
27		Kogarah	New South Wales	Australia	2217
28		Lismore	New South Wales	Australia	2480
29		St Leonards	New South Wales	Australia	2065
30		Sydney	New South Wales	Australia	2031
31		Sydney	New South Wales	Australia	2139
32		Sydney	New South Wales	Australia	2229
33		Brisbane	Queensland	Australia	4029
34		Redcliffe	Queensland	Australia	4020
35		Southport	Queensland	Australia	4215
36		Woolloongabba	Queensland	Australia	4102
37		Adelaide	South Australia	Australia	5042
38		Woodville South	South Australia	Australia	5011
39		Box Hill	Victoria	Australia	3128
40		Clayton	Victoria	Australia	3168
41		Geelong	Victoria	Australia	3220
42		Melbourne	Victoria	Australia	3135
43		Melbourne	Victoria	Australia	3181
44		Fremantle	Western Australia	Australia	6160
45		Perth	Western Australia	Australia	6000
46		Graz	Steiermark	Austria	8036
47		Feldkirch	Vorarlberg	Austria	6807
48		Innsbruck		Austria	6020
49		Salzburg		Austria	5020
50		Wien		Austria	1090
51		Wien		Austria	1140
52		Bruxelles - Brussel		Belgium	1070
53		Bruxelles - Brussel		Belgium	1200
54		Duffel		Belgium	2570
55		Genk		Belgium	3600
56		Gent		Belgium	9000
57		Hasselt		Belgium	3500
58		Leuven		Belgium	3000
59		Liege		Belgium	4000
60		Lier		Belgium	2500
61		Namur		Belgium	5000
62		Yvoir		Belgium	5530
63		Zottegem		Belgium	9620
64		Uberaba	Minas Gerais	Brazil	38010 380
65		Curitiba	Parana	Brazil	80050-350
66		Londrina	Parana	Brazil	86038440
67		Botucatu	Sao Paulo	Brazil	18618 000
68		Sorocaba	Sao Paulo	Brazil	18031-000
69		São Paulo	Sao Paulo	Brazil	04039-004
70		Sao Paulo	SP	Brazil	01509-900
71		Sao Paulo	SP	Brazil	04023-061
72		São Paulo	SP	Brazil	01323-001
73		Rio de Janeiro		Brazil
74		Winnipeg	Manitoba	Canada	R2H 2A6
75		London	Ontario	Canada	N6A 4G5
76		Ottawa	Ontario	Canada	K1Y 4E9
77		Toronto	Ontario	Canada	M4N 3M5
78		Toronto	Ontario	Canada	M6R 1B5
79		Guangzhou	Guangdong	China	510000
80		Guangzhou	Guangdong	China	510120
81		Harbin	Heilongjiang	China	150086
82		Wuhan	Hubei	China	430022
83		Suzhou	Jiangsu	China	215004
84		Shenyang	Liaoning	China	110016
85		Hangzhou	Zhejiang	China	310016
86		Beijing		China	100020
87		Beijing		China	100029
88		Beijing		China	100037
89		Beijing		China	100038
90		Beijing		China	100044
91		Beijing		China	100730
92		Beijing		China	100853
93		Shanghai		China	200001
94		Shanghai		China	200032
95		Shanghai		China	200433
96		Karlovy Vary		Czech Republic	360 00
97		Kladno		Czech Republic	27259
98		Ostrava-Poruba		Czech Republic	708 52
99		Ostrava		Czech Republic	728 80
100		Prague 5		Czech Republic	150 00
101		Prague		Czech Republic	140 21
102		Praha 1		Czech Republic	110 00
103		Praha 2		Czech Republic	12800
104		Usti nad Lebem		Czech Republic	401 13
105		Aarhus C		Denmark	8000
106		Braedstrup		Denmark	8740
107		Frederiksberg		Denmark	2000F
108		Hellerup		Denmark	2900
109		Seinäjoki		Finland	60220
110		Agen Cedex 9		France	47923
111		Amiens		France	80000
112		Angers Cedex 01		France	49033
113		Arras		France	62000
114		Besancon		France	25000
115		Bordeaux		France	33000
116		Brest Cedex		France	29609
117		Castelnau Le Lez		France	34170
118		Clamart		France	92141
119		Clermont Ferrand		France	63000
120		Colombes Cedex		France	92701
121		Creteil		France	94000
122		Dijon		France	21000
123		Grenoble		France	38028
124		Grenoble		France	38043
125		Lille Cedex		France	59037
126		Limoges		France	87042
127		Metz-tessy		France	74370
128		Montpellier Cedex		France	34295
129		Nantes		France	44000
130		Nice		France	06002
131		Nimes Cedex 9		France	30029
132		Orthez		France	64300
133		Paris Cedex 15		France	75908
134		Paris		France	75004
135		Paris		France	75015
136		Paris		France	75475
137		Paris		France	75877
138		Pierre Benite		France	69495
139		Roanne		France	42328
140		Rouen Cedex		France	76031
141		Saint Etienne		France	42055
142		Strasbourg Cedex		France	67091
143		Toulon		France	83000
144		Toulouse		France	31403
145		Tours		France	37044
146		Valenciennes Cedex		France	59322
147		Vandoeuvre Les Nancy		France	54511
148		Vernon		France	27200
149		Bruchsal	Baden-Württemberg	Germany	76646
150		Heidelberg	Baden-Württemberg	Germany	69115
151		Karlsbad	Baden-Württemberg	Germany	76307
152		Mannheim	Baden-Württemberg	Germany	68167
153		Neckargemünd	Baden-Württemberg	Germany	69151
154		Tübingen	Baden-Württemberg	Germany	72076
155		Augsburg	Bayern	Germany	86156
156		München	Bayern	Germany	80331
157		München	Bayern	Germany	81377
158		Würzburg	Bayern	Germany	97080
159		Darmstadt	Hessen	Germany	64297
160		Frankfurt	Hessen	Germany	60590
161		Frankfurt	Hessen	Germany	60596
162		Gießen	Hessen	Germany	35392
163		Wiesbaden	Hessen	Germany	65183
164		Greifswald	Mecklenburg-Vorpommern	Germany	17475
165		Hannover	Niedersachsen	Germany	30625
166		Rotenburg	Niedersachsen	Germany	27342
167		Düsseldorf	Nordrhein-Westfalen	Germany	40225
168		Essen	Nordrhein-Westfalen	Germany	45122
169		Paderborn	Nordrhein-Westfalen	Germany	33098
170		Soest	Nordrhein-Westfalen	Germany	59494
171		Witten	Nordrhein-Westfalen	Germany	58455
172		Mainz	Rheinland-Pfalz	Germany	55131
173		Homburg	Saarland	Germany	66421
174		Homburg	Saarland	Germany	66424
175		Halle	Sachsen-Anhalt	Germany	06120
176		Magdeburg	Sachsen-Anhalt	Germany	39112
177		Dresden	Sachsen	Germany	01307
178		Leipzig	Sachsen	Germany	04289
179		Berlin		Germany	10713
180		Berlin		Germany	12099
181		Hamburg		Germany	20251
182		Hong Kong		Hong Kong
183		Wanchai		Hong Kong
184		Budapest		Hungary	1096
185		Budapest		Hungary	1115
186		Debrecen		Hungary	4032
187		Kecskemet		Hungary	6000
188		Kistarcsa		Hungary	2143
189		Miskolc		Hungary	3526
190		Szentes		Hungary	6600
191		Szombathely		Hungary	9700
192		Kochi	Kerala	India	682026
193		Mumbai	Maharashtra	India	400016
194		Hyderabad		India	500082
195		Kolkata		India	700029
196		New Delhi		India	110060
197		Pune		India	411001
198		Bandung		Indonesia	40161
199		Jakarta		Indonesia	10330
200		Jakarta		Indonesia	10430
201		Medan		Indonesia	20152
202		Semarang		Indonesia	50241
203		Afula		Israel	18101
204		Ashkelon		Israel	78306
205		Beer Sheva		Israel	84101
206		Haifa		Israel	31048
207		Haifa		Israel	31096
208		Haifa		Israel	34362
209		Holon		Israel	58100
210		Jerusalem		Israel	91120
211		Kfar Saba		Israel	44281
212		Petach Tikva		Israel	49100
213		Rehovot		Israel	76100
214		Safed		Israel	13100
215		Tel Aviv		Israel	64239
216		Bologna		Italy	40138
217		Chieti		Italy	66013
218		Cremona		Italy	26100
219		Milano		Italy	20122
220		Milano		Italy	20132
221		Milano		Italy	20142
222		Napoli		Italy	80131
223		Padova		Italy	35128
224		Palermo		Italy	90127
225		Parma		Italy	43100
226		Pavia		Italy	27100
227		Piacenza		Italy	29100
228		Reggio Emilia		Italy	42100
229		Varese		Italy	21100
230		Venezia		Italy	30122
231		Seoul	Korea	Korea, Republic of	110-744
232		Daegu		Korea, Republic of	700721
233		Daegu		Korea, Republic of	705-718
234		Seoul		Korea, Republic of	120-752
235		Seoul		Korea, Republic of	137-701
236		Taegu		Korea, Republic of	700-712
237		Selangor		Malaysia	68000
238		Amsterdam		Netherlands	1105 AZ
239		Arnhem		Netherlands	6815 AD
240		Dordrecht		Netherlands	3318 AT
241		Enschede		Netherlands	7511 JX
242		Groningen		Netherlands	9713 GZ
243		Hoofddorp		Netherlands	2134 TM
244		Maastricht		Netherlands	6229 HX
245		Rotterdam		Netherlands	3083 AN
246		Zwijndrecht		Netherlands	3331 LZ
247		Zwolle		Netherlands	8025 AB
248		Auckland		New Zealand	0622
249		Auckland		New Zealand	1023
250		Auckland		New Zealand	2024
251		Christchurch		New Zealand	8011
252		Palmerston North		New Zealand	4414
253		Wellington South		New Zealand	6021
254		Fredrikstad		Norway	1603
255		Oslo		Norway	0407
256		Rud		Norway	1309
257		Trondheim		Norway	7006
258		Quezon City		Philippines	0850
259		Quezon City		Philippines	1102
260		Bialystok		Poland	15-276
261		Bydgoszcz		Poland	85-168
262		Gdansk		Poland	80-952
263		Katowice		Poland	40-365
264		Krakow		Poland	31-066
265		Lodz		Poland	90-153
266		Lublin		Poland	20-081
267		Poznan		Poland	60-631
268		Poznan		Poland	61-848
269		Torun		Poland	87-100
270		Warszawa		Poland	01-138
271		Warszawa		Poland	02-097
272		Warszawa		Poland	04-479
273		Wroclaw		Poland	50-326
274		Wroclaw		Poland	51-124
275		San Juan		Puerto Rico	00927
276		Singapore		Singapore	169608
277		Singapore		Singapore	308433
278		Cape Town	Cape	South Africa	7500
279		Johannesburg	Gauteng	South Africa	1724
280		Johannesburg	Gauteng	South Africa	2132
281		Johannesburg	Gauteng	South Africa	2157
282		Johannesburg	Gauteng	South Africa	2191
283		Johannesburg	Gauteng	South Africa	2193
284		Pretoria	Gauteng	South Africa	0084
285		Pretoria	Gauteng	South Africa	0157
286		Pretoria	Gauteng	South Africa	0181
287		Cape Town	Western Cape	South Africa	7460
288		Somerset West	Western Cape	South Africa	7130
289		Worcester	Western Cape	South Africa	6850
290		Terrassa	Barcelona	Spain	08221
291		Alcorcón	Madrid	Spain	28922
292		Fuenlabrada	Madrid	Spain	28942
293		Xàtiva	Valencia	Spain	46800
294		Barcelona		Spain	08025
295		Barcelona		Spain	08036
296		Girona		Spain	17007
297		Madrid		Spain	28034
298		Pamplona		Spain	31008
299		Borås		Sweden	501 82
300		Göteborg		Sweden	413 45
301		Göteborg		Sweden	416 85
302		Jönköping		Sweden	551 85
303		Sundsvall		Sweden	851 86
304		Västervik		Sweden	593 81
305		Genéve 14	Genève 14	Switzerland	1211
306		Chur	Graubünden	Switzerland	7000
307		Lausanne	Waadt	Switzerland	1005
308		Lausanne	Waadt	Switzerland	1011
309		Luzern		Switzerland	6000
310		Zürich		Switzerland	8091
311		Kaosiung	Kaoshiong	Taiwan	807
312		Taichung		Taiwan	40705
313		Taipei		Taiwan	10016
314		Taipei		Taiwan	112
315		Taipei		Taiwan	220
316		Bangkok		Thailand	10400
317		Bangkok		Thailand	10700
318		Pathumwan, Bangkok		Thailand	10330
319		Plymouth	Devon	United Kingdom	PL6 8DH
320		Chelmsford	Essex	United Kingdom	CM1 5ET
321		Isleworth	Greater London	United Kingdom	TW7 6AF
322		London	Greater London	United Kingdom	SE1 7EH
323		London	Greater London	United Kingdom	SE5 9RS
324		London		United Kingdom

Sponsors and Collaborators

• Bayer
• Johnson & Johnson Pharmaceutical Research & Development, 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: NCT00440193
• Other Study ID Numbers: 11702a; 2006-004495-13; 11702b
• First Posted: Feb 26, 2007
• Last Update Posted: Feb 27, 2014
• Last Verified: Jan 1, 2014

• Additional relevant MeSH terms: Thrombosis; Venous Thrombosis; Enoxaparin; Rivaroxaban

Study Results

Participant Flow

Recruitment Details	Participants with confirmed acute proximal symptomatic deep vein thrombosis (DVT) without symptomatic pulmonary embolism (PE) were recruited at specialized study sites.
Pre-assignment Detail	Out of 3459 participants screened, 10 failed screening due to protocol violations, and 3449 participants were randomized (1731 to rivaroxaban and 1718 to enoxaparin/VKA).

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Enoxaparin/VKA
Arm/Group Description	Participants were to receive rivaroxaban 15 mg oral tablet twice daily for 3 weeks, followed by 20 mg once daily	Participants were to receive 1.0 mg/kg enoxaparin twice daily (subcutaneous) for at least 5 days, plus vitamin K antagonist (VKA) (oral) at individually titrated doses to achieve a target international normalized ratio (INR) of 2.5 (range: 2.0 to 3.0)
Period Title: Treatment Period
STARTED	1731	1718
Participants Received Treatment	1718	1711
COMPLETED	1426	1367
NOT COMPLETED	305	351
Period Title: Treatment Period
STARTED	1425	1407
COMPLETED	1380	1369
NOT COMPLETED	45	38

Baseline Characteristics

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Enoxaparin/VKA	Total
Arm/Group Description	Participants were to receive rivaroxaban 15 mg oral tablet twice daily for 3 weeks, followed by 20 mg once daily	Participants were to receive 1.0 mg/kg enoxaparin twice daily (subcutaneous) for at least 5 days, plus vitamin K antagonist (VKA) (oral) at individually titrated doses to achieve a target international normalized ratio (INR) of 2.5 (range: 2.0 to 3.0)	Total of all reporting groups
Overall Participants	1731	1718	3449
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.8 (16.4)	56.4 (16.3)	56.1 (16.4)
Age, Customized (participants) [Number]
18 - < 40 years	314 18.1%	279 16.2%	593 17.2%
40 - < 60 years	642 37.1%	662 38.5%	1304 37.8%
60 - < 75 years	530 30.6%	519 30.2%	1049 30.4%
≥ 75 years	245 14.2%	258 15%	503 14.6%
Sex: Female, Male (Count of Participants)
Female	738 42.6%	751 43.7%	1489 43.2%
Male	993 57.4%	967 56.3%	1960 56.8%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Symptomatic Recurrent Venous Thromboembolism [VTE] (i.e. the Composite of Recurrent Deep Vein Thrombosis [DVT] or Fatal or Non-fatal Pulmonary Embolism [PE]) Until the Intended End of Study Treatment
Description	All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound (for DVT), venography (for DVT), spiral computed tomography (CT) scanning (for PE), pulmonary angiography (for PE), ventilation/perfusion lung scan (for PE), lung scintigraphy (for PE), autopsy (for fatal PE) or unexplained death for which DVT/PE could not be ruled out (for fatal PE), and/or case summaries.
Time Frame	3-, 6- or 12-month study treatment period

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) population consisted of all randomized participants with valid informed consent. Participants were analyzed according to the treatment assigned at randomization.

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Enoxaparin/VKA
Arm/Group Description	Participants were to receive rivaroxaban 15 mg oral tablet twice daily for 3 weeks, followed by 20 mg once daily	Participants were to receive 1.0 mg/kg enoxaparin twice daily (subcutaneous) for at least 5 days, plus vitamin K antagonist (VKA) (oral) at individually titrated doses to achieve a target international normalized ratio (INR) of 2.5 (range: 2.0 to 3.0)
Measure Participants	1731	1718
Number [Percentage of participants]	2.1 0.1%	3.0 0.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban (Xarelto, BAY59-7939), Enoxaparin/VKA
	Comments	The rivaroxaban to comparator hazard ratio was computed with a 95% CI (confidence interval) (two-sided testing). Based on this model, rivaroxaban would be considered at least as effective as the comparator if the upper limit of the CI was less than 2.0.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Assuming equal efficacy, a total of 88 events was calculated to give a power of 90% to prove that rivaroxaban is at least as effective as the comparator, considering a non-inferiority upper CI margin for the hazard ratio of 2.0 (two-sided α=0.05). A mean incidence for the primary efficacy outcome of 3% was expected and at least 1465 participants per group were determined to be necessary. This number was to be adjusted based on the observed overall incidence of symptomatic recurrent VTE.
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Regression, Cox
	Comments	Stratified by intend treatment duration, adjusted for presence of active malignancy at baseline
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.68
	Confidence Interval	() 95%; 0.44 to 1.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.2179
	Estimation Comments	The standard error of the log hazard ratio was estimated.

2. Secondary Outcome

Title	Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality Until the Intended End of Study Treatment
Description	All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound (for DVT), venography (for DVT), spiral computed tomography (CT) scanning (for PE), pulmonary angiography (for PE), ventilation/perfusion lung scan (for PE), lung scintigraphy (for PE), autopsy (for deaths), results/films/images of confirmatory testing, and/or case summaries.
Time Frame	3-, 6- or 12-month study treatment period

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) population consisted of all randomized participants with valid informed consent. Participants were analyzed according to the treatment assigned at randomization.

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Enoxaparin/VKA
Arm/Group Description	Participants were to receive rivaroxaban 15 mg oral tablet twice daily for 3 weeks, followed by 20 mg once daily	Participants were to receive 1.0 mg/kg enoxaparin twice daily (subcutaneous) for at least 5 days, plus vitamin K antagonist (VKA) (oral) at individually titrated doses to achieve a target international normalized ratio (INR) of 2.5 (range: 2.0 to 3.0)
Measure Participants	1731	1718
Number [Percentage of participants]	4.0 0.2%	5.1 0.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban (Xarelto, BAY59-7939), Enoxaparin/VKA
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.044
	Comments	Nominal p-value
	Method	Regression, Cox
	Comments	Stratified by intend treatment duration, adjusted for presence of active malignancy at baseline.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.72
	Confidence Interval	() 95%; 0.53 to 0.99
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1616
	Estimation Comments	The standard error of the log hazard ratio was estimated.

3. Secondary Outcome

Title	Percentage of Participants With an Event for Net Clinical Benefit 1 Until the Intended End of Study Treatment
Description	Net clinical benefit 1: composite of recurrent DVT or non-fatal or fatal PE, and major bleeding. Major bleeding was overt bleeding associated with 2 g/dL or greater fall in hemoglobin, leading to a transfusion of ≥2 units, occurring in a critical site or contributing to death. Net clinical benefit was considered greater in those participants with fewer composite events. All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment, based on either compression ultrasound, venography, spiral computed tomography scanning, pulmonary angiography, ventilation/perfusion lung scan, lung scintigraphy, autopsy or unexplained death for which DVT/PE could not be ruled out, results/films/images of confirmatory testing, and/or case summaries.
Time Frame	3-, 6- or 12-month study treatment period

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) population consisted of all randomized participants with valid informed consent. Participants were analyzed according to the treatment assigned at randomization.

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Enoxaparin/VKA
Arm/Group Description	Participants were to receive rivaroxaban 15 mg oral tablet twice daily for 3 weeks, followed by 20 mg once daily	Participants were to receive 1.0 mg/kg enoxaparin twice daily (subcutaneous) for at least 5 days, plus vitamin K antagonist (VKA) (oral) at individually titrated doses to achieve a target international normalized ratio (INR) of 2.5 (range: 2.0 to 3.0)
Measure Participants	1731	1718
Number [Percentage of participants]	2.9 0.2%	4.2 0.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban (Xarelto, BAY59-7939), Enoxaparin/VKA
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.027
	Comments	Nominal p-value
	Method	Regression, Cox
	Comments	Stratified by intend treatment duration, adjusted for presence of active malignancy at baseline.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.67
	Confidence Interval	() 95%; 0.47 to 0.95
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1828
	Estimation Comments	The standard error of the log hazard ratio was estimated.

4. Secondary Outcome

Title	Percentage of Participants With Recurrent DVT Until the Intended End of Study Treatment
Description	All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound, venography, results/films/images of confirmatory testing, and/or case summaries.
Time Frame	3-, 6- or 12-month study treatment period

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) population consisted of all randomized participants with valid informed consent. Participants were analyzed according to the treatment assigned at randomization.

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Enoxaparin/VKA
Arm/Group Description	Participants were to receive rivaroxaban 15 mg oral tablet twice daily for 3 weeks, followed by 20 mg once daily	Participants were to receive 1.0 mg/kg enoxaparin twice daily (subcutaneous) for at least 5 days, plus vitamin K antagonist (VKA) (oral) at individually titrated doses to achieve a target international normalized ratio (INR) of 2.5 (range: 2.0 to 3.0)
Measure Participants	1731	1718
Number [Percentage of participants]	0.9 0.1%	1.6 0.1%

5. Secondary Outcome

Title	Percentage of Participants With Clinically Relevant Bleeding, Treatment-emergent (Time Window: Until 2 Days After Last Dose)
Description	All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Clinically relevant bleeding included major bleeding (overt bleeding associated with 2 g/dL or greater fall in hemoglobin, 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) and non-major bleeding associated with medical intervention, unscheduled physician contact, (temporary) cessation of study treatment, discomfort for the participants such as pain, or impairment of activities of daily life.
Time Frame	3-, 6- or 12-month study treatment period

Outcome Measure Data

Analysis Population Description

The valid-for-safety analysis population consisted of all participants who were randomized with valid informed consent and received at least one dose of anticoagulant study treatment after randomization (i.e. enoxaparin, warfarin, acenocoumarol, rivaroxaban). Participants were analyzed according to the treatment they actually received.

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Enoxaparin/VKA
Arm/Group Description	Participants were to receive rivaroxaban 15 mg oral tablet twice daily for 3 weeks, followed by 20 mg once daily	Participants were to receive 1.0 mg/kg enoxaparin twice daily (subcutaneous) for at least 5 days, plus vitamin K antagonist (VKA) (oral) at individually titrated doses to achieve a target international normalized ratio (INR) of 2.5 (range: 2.0 to 3.0)
Measure Participants	1718	1711
Number [Percentage of participants]	8.1 0.5%	8.1 0.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban (Xarelto, BAY59-7939), Enoxaparin/VKA
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.77
	Comments	Nominal p-value
	Method	Regression, Cox
	Comments	Stratified by intend treatment duration, adjusted for presence of active malignancy at baseline.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.97
	Confidence Interval	() 95%; 0.76 to 1.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1204
	Estimation Comments	The standard error of the log hazard ratio was estimated.

6. Secondary Outcome

Title	Percentage of Participants With All Deaths
Description	All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either autopsy, results/films/images of confirmatory testing, and/or case summaries.
Time Frame	3-, 6- or 12-month study treatment period

Outcome Measure Data

Analysis Population Description

The valid-for-safety analysis population consisted of all participants who were randomized with valid informed consent and received at least one dose of anticoagulant study treatment after randomization (i.e. enoxaparin, warfarin, acenocoumarol, rivaroxaban). Participants were analyzed according to the treatment they actually received.

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Enoxaparin/VKA
Arm/Group Description	Participants were to receive rivaroxaban 15 mg oral tablet twice daily for 3 weeks, followed by 20 mg once daily	Participants were to receive 1.0 mg/kg enoxaparin twice daily (subcutaneous) for at least 5 days, plus vitamin K antagonist (VKA) (oral) at individually titrated doses to achieve a target international normalized ratio (INR) of 2.5 (range: 2.0 to 3.0)
Measure Participants	1718	1711
All post-randomization	2.4 0.1%	3.0 0.2%
Treatment-emergent (time window: 2 days)	1.0 0.1%	1.1 0.1%
Treatment-emergent (time window: 7 days)	1.2 0.1%	1.5 0.1%

7. Secondary Outcome

Title	Percentage of Participants With Other Vascular Events, On-treatment (Time Window: Until 1 Day After Last Dose)
Description	All pre-defined vascular events (ST segment elevation myocardial infarction, non ST segment elevation myocardial infarction, unstable angina, ischemic stroke, transient ischemic attack, non-central nervous system systemic embolism or vascular death) were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based results/films/images of confirmatory testing, and/or case summaries.
Time Frame	3-, 6- or 12-month study treatment period

Outcome Measure Data

Analysis Population Description

The valid-for-safety analysis population consisted of all participants who were randomized with valid informed consent and received at least one dose of anticoagulant study treatment after randomization (i.e. enoxaparin, warfarin, acenocoumarol, rivaroxaban). Participants were analyzed according to the treatment they actually received.

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Enoxaparin/VKA
Arm/Group Description	Participants were to receive rivaroxaban 15 mg oral tablet twice daily for 3 weeks, followed by 20 mg once daily	Participants were to receive 1.0 mg/kg enoxaparin twice daily (subcutaneous) for at least 5 days, plus vitamin K antagonist (VKA) (oral) at individually titrated doses to achieve a target international normalized ratio (INR) of 2.5 (range: 2.0 to 3.0)
Measure Participants	1718	1711
Number [Percentage of participants]	0.7 0%	0.8 0%

8. Other Pre-specified Outcome

Title	Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment
Description	All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment, based on either compression ultrasound, venography, spiral computed tomography scanning, pulmonary angiography, ventilation/perfusion lung scan, lung scintigraphy, autopsy or unexplained death for which DVT/PE could not be ruled out, results/films/images of confirmatory testing, and/or case summaries. Major bleeding was overt bleeding associated with 2 g/dL or greater fall in hemoglobin, leading to a transfusion of ≥2 units, occurring in a critical site or contributing to death.
Time Frame	3-, 6- or 12-month study treatment period

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) population consisted of all randomized participants with valid informed consent. Participants were analyzed according to the treatment assigned at randomization.

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Enoxaparin/VKA
Arm/Group Description	Participants were to receive rivaroxaban 15 mg oral tablet twice daily for 3 weeks, followed by 20 mg once daily	Participants were to receive 1.0 mg/kg enoxaparin twice daily (subcutaneous) for at least 5 days, plus vitamin K antagonist (VKA) (oral) at individually titrated doses to achieve a target international normalized ratio (INR) of 2.5 (range: 2.0 to 3.0)
Measure Participants	1731	1718
Death (PE)	0.06 0%	0 0%
Death (PE cannot be excluded)	0.2 0%	0.3 0%
Symptomatic PE and DVT	0.06 0%	0 0%
Symptomatic recurrent PE only	1.2 0.1%	1.0 0.1%
Symptomatic recurrent DVT only	0.8 0%	1.6 0.1%
Death (bleeding)	0.06 0%	0.3 0%
Death (cardiovascular)	0.1 0%	0.2 0%
Death (other)	1.8 0.1%	2.0 0.1%
Major bleeding	0.9 0.1%	1.3 0.1%

9. Other Pre-specified Outcome

Title	Percentage of Participants With Symptomatic Recurrent Venous Thromboembolism [VTE] (i.e. the Composite of Recurrent Deep Vein Thrombosis [DVT] or Fatal or Non-fatal Pulmonary Embolism [PE]) During Observational Period
Description	All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound (for DVT), venography (for DVT), spiral computed tomography (CT) scanning (for PE), pulmonary angiography (for PE), ventilation/perfusion lung scan (for PE), lung scintigraphy (for PE), autopsy (for fatal PE) or unexplained death for which DVT/PE could not be ruled out (for fatal PE), results/films/images of confirmatory testing, and/or case summaries.
Time Frame	Up to 30 days after the last intake of study medication

Outcome Measure Data

Analysis Population Description

Participants entering the observational period were participants for whom the investigator indicated on the eCRF (electronic case report form) that the participant entered the observational period or had a confirmed event more than one day and up to 30 days after the last dose as a component of the respective composite outcome.

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Enoxaparin/VKA
Arm/Group Description	Participants were to receive rivaroxaban 15 mg oral tablet twice daily for 3 weeks, followed by 20 mg once daily	Participants were to receive 1.0 mg/kg enoxaparin twice daily (subcutaneous) for at least 5 days, plus vitamin K antagonist (VKA) (oral) at individually titrated doses to achieve a target international normalized ratio (INR) of 2.5 (range: 2.0 to 3.0)
Measure Participants	1425	1408
Number [Percentage of participants]	0.8 0%	0.5 0%

10. Other Pre-specified Outcome

Title	Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality During Observational Period
Description	All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound (for DVT), venography (for DVT), spiral computed tomography (CT) scanning (for PE), pulmonary angiography (for PE), ventilation/perfusion lung scan (for PE), lung scintigraphy (for PE), autopsy (for deaths), results/films/images of confirmatory testing, and/or case summaries.
Time Frame	Up to 30 days after the last intake of study medication

Outcome Measure Data

Analysis Population Description

Participants entering the observational period were participants for whom the investigator indicated on the eCRF that the participant entered the observational period or had a confirmed event more than one day and up to 30 days after the last dose as a component of the respective composite outcome.

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Enoxaparin/VKA
Arm/Group Description	Participants were to receive rivaroxaban 15 mg oral tablet twice daily for 3 weeks, followed by 20 mg once daily	Participants were to receive 1.0 mg/kg enoxaparin twice daily (subcutaneous) for at least 5 days, plus vitamin K antagonist (VKA) (oral) at individually titrated doses to achieve a target international normalized ratio (INR) of 2.5 (range: 2.0 to 3.0)
Measure Participants	1430	1413
Number [Percentage of participants]	2.2 0.1%	1.8 0.1%

11. Other Pre-specified Outcome

Title	Percentage of Participants With an Event for Net Clinical Benefit 1 During Observational Period
Description	Net clinical benefit 1: composite of recurrent DVT or non-fatal or fatal PE or major bleeding. Major bleeding was overt bleeding associated with 2 g/dL or greater fall in hemoglobin, leading to a transfusion of ≥2 units, occurring in a critical site or contributing to death. Net clinical benefit was considered greater in those participants with fewer composite events. All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment, based on either compression ultrasound, venography, spiral computed tomography scanning, pulmonary angiography, ventilation/perfusion lung scan, lung scintigraphy, autopsy or unexplained death for which DVT/PE could not be ruled out, results/films/images of confirmatory testing, and/or case summaries.
Time Frame	Up to 30 days after the last intake of study medication

Outcome Measure Data

Analysis Population Description

Participants entering the observational period were participants for whom the investigator indicated on the eCRF that the participant entered the observational period or had a confirmed event more than one day and up to 30 days after the last dose as a component of the respective composite outcome.

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Enoxaparin/VKA
Arm/Group Description	Participants were to receive rivaroxaban 15 mg oral tablet twice daily for 3 weeks, followed by 20 mg once daily	Participants were to receive 1.0 mg/kg enoxaparin twice daily (subcutaneous) for at least 5 days, plus vitamin K antagonist (VKA) (oral) at individually titrated doses to achieve a target international normalized ratio (INR) of 2.5 (range: 2.0 to 3.0)
Measure Participants	1425	1410
Number [Percentage of participants]	1.1 0.1%	1.1 0.1%

12. Other Pre-specified Outcome

Title	Percentage of Participants With Recurrent DVT During Observational Period
Description	All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound, venography, results/films/images of confirmatory testing, and/or case summaries.
Time Frame	Up to 30 days after the last intake of study medication

Outcome Measure Data

Analysis Population Description

Participants entering the observational period were participants for whom the investigator indicated on the eCRF that the participant entered the observational period or had a confirmed event more than one day and up to 30 days after the last dose as a component of the respective composite outcome.

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Enoxaparin/VKA
Arm/Group Description	Participants were to receive rivaroxaban 15 mg oral tablet twice daily for 3 weeks, followed by 20 mg once daily	Participants were to receive 1.0 mg/kg enoxaparin twice daily (subcutaneous) for at least 5 days, plus vitamin K antagonist (VKA) (oral) at individually titrated doses to achieve a target international normalized ratio (INR) of 2.5 (range: 2.0 to 3.0)
Measure Participants	1425	1408
Number [Percentage of participants]	0.6 0%	0.3 0%

13. Other Pre-specified Outcome

Title	Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period
Description	All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment, based on either compression ultrasound, venography, spiral computed tomography scanning, pulmonary angiography, ventilation/perfusion lung scan, lung scintigraphy, autopsy or unexplained death for which DVT/PE could not be ruled out, results/films/images of confirmatory testing, and/or case summaries. Major bleeding was overt bleeding associated with 2 g/dL or greater fall in hemoglobin, leading to a transfusion of ≥2 units, occurring in a critical site or contributing to death.
Time Frame	Up to 30 days after the last intake of study medication

Outcome Measure Data

Analysis Population Description

Participants entering the observational period were participants for whom the investigator indicated on the eCRF that the participant entered the observational period or had a confirmed event more than one day and up to 30 days after the last dose as a component of the respective composite outcome.

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Enoxaparin/VKA
Arm/Group Description	Participants were to receive rivaroxaban 15 mg oral tablet twice daily for 3 weeks, followed by 20 mg once daily	Participants were to receive 1.0 mg/kg enoxaparin twice daily (subcutaneous) for at least 5 days, plus vitamin K antagonist (VKA) (oral) at individually titrated doses to achieve a target international normalized ratio (INR) of 2.5 (range: 2.0 to 3.0)
Measure Participants	1425	1408
Death (PE)	0 0%	0 0%
Death (PE cannot be excluded)	0.07 0%	0.07 0%
Symptomatic PE and DVT	0 0%	0 0%
Symptomatic recurrent PE only	0.3 0%	0.1 0%
Symptomatic recurrent DVT only	0.6 0%	0.3 0%
Death (bleeding)	0.07 0%	0.1 0%
Death (cardiovascular)	0.07 0%	0.3 0%
Death (other)	1.3 0.1%	0.8 0%
Major bleeding	0.2 0%	0.6 0%

14. Post-Hoc Outcome

Title	Percentage of Participants With an Event for Net Clinical Benefit 2 Until the Intended End of Study Treatment
Description	Net clinical benefit 2: composite of recurrent DVT or non-fatal or fatal PE, major bleeding. Major bleeding was overt bleeding associated with 2 g/dL or greater fall in hemoglobin, leading to transfusion of ≥2 units, occurring in a critical site or contributing to death, cardiovascular death, myocardial infarction, stroke, and non CNS (central nervous system) systemic embolism. Net clinical benefit was considered greater in those participants with fewer composite events. All events confirmed by independent committee blinded to treatment, based on compression ultrasound, venography, spiral CT scan, pulmonary angiography, ventilation/perfusion lung scan, lung scintigraphy, autopsy, results/films/images of confirmatory testing and/or case summaries
Time Frame	3-, 6- or 12-month study treatment period

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) population consisted of all randomized participants with valid informed consent. Participants were analyzed according to the treatment assigned at randomization.

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Enoxaparin/VKA
Arm/Group Description	Participants were to receive rivaroxaban 15 mg oral tablet twice daily for 3 weeks, followed by 20 mg once daily	Participants were to receive 1.0 mg/kg enoxaparin twice daily (subcutaneous) for at least 5 days, plus vitamin K antagonist (VKA) (oral) at individually titrated doses to achieve a target international normalized ratio (INR) of 2.5 (range: 2.0 to 3.0)
Measure Participants	1731	1718
Number [Percentage of participants]	3.6 0.2%	4.7 0.3%

15. Post-Hoc Outcome

Title	Percentage of Participants With an Event for Net Clinical Benefit 2 During Observational Period
Description	Net clinical benefit 2: composite of recurrent DVT or non-fatal or fatal PE, major bleeding, cardiovascular death, myocardial infarctions, stroke, or non CNS systemic embolism. Major bleeding was associated with 2 g/dL or greater fall in hemoglobin, leading to a transfusion of ≥2 units, occurring in a critical site or contributing to death. Net clinical benefit was considered greater in those participants with fewer composite events. All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment, based on either compression ultrasound (DVT), venography (DVT), spiral CT scanning (PE), pulmonary angiography ( PE), ventilation/perfusion lung scan (PE), lung scintigraphy (PE), autopsy or unexplained death for which DVT/PE could not be ruled out, results/films/images of confirmatory testing, and/or case summaries.
Time Frame	Up to 30 days after the last intake of study medication

Outcome Measure Data

Analysis Population Description

Participants entering the observational period were participants for whom the investigator indicated on the eCRF that the participant entered the observational period or had a confirmed event more than one day and up to 30 days after the last dose as a component of the respective composite outcome.

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)	Enoxaparin/VKA
Arm/Group Description	Participants were to receive rivaroxaban 15 mg oral tablet twice daily for 3 weeks, followed by 20 mg once daily	Participants were to receive 1.0 mg/kg enoxaparin twice daily (subcutaneous) for at least 5 days, plus vitamin K antagonist (VKA) (oral) at individually titrated doses to achieve a target international normalized ratio (INR) of 2.5 (range: 2.0 to 3.0)
Measure Participants	1426	1410
Number [Percentage of participants]	1.2 0.1%	1.3 0.1%

Adverse Events

Arm/Group Title	Rivaroxaban (Xarelto, BAY59-7939)		Enoxaparin/VKA
Arm/Group Description	Participants were to receive rivaroxaban 15 mg oral tablet twice daily for 3 weeks, followed by 20 mg once daily		Participants were to receive 1.0 mg/kg enoxaparin twice daily (subcutaneous) for at least 5 days, plus vitamin K antagonist (VKA) (oral) at individually titrated doses to achieve a target international normalized ratio (INR) of 2.5 (range: 2.0 to 3.0)
All Cause Mortality
	Rivaroxaban (Xarelto, BAY59-7939)		Enoxaparin/VKA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Rivaroxaban (Xarelto, BAY59-7939)		Enoxaparin/VKA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	222/1718 (12.9%)		252/1711 (14.7%)
Blood and lymphatic system disorders
Anaemia	11/1718 (0.6%)		8/1711 (0.5%)
Febrile neutropenia	1/1718 (0.1%)		0/1711 (0%)
Lymphadenopathy mediastinal	0/1718 (0%)		1/1711 (0.1%)
Microcytic anaemia	1/1718 (0.1%)		0/1711 (0%)
Normochromic normocytic anaemia	1/1718 (0.1%)		0/1711 (0%)
Splenic haemorrhage	0/1718 (0%)		1/1711 (0.1%)
Thrombocytopenia	2/1718 (0.1%)		1/1711 (0.1%)
Autoimmune thrombocytopenia	0/1718 (0%)		1/1711 (0.1%)
Haemorrhagic anaemia	0/1718 (0%)		1/1711 (0.1%)
Spontaneous haematoma	1/1718 (0.1%)		0/1711 (0%)
Cardiac disorders
Acute myocardial infarction	5/1718 (0.3%)		1/1711 (0.1%)
Angina pectoris	0/1718 (0%)		1/1711 (0.1%)
Angina unstable	1/1718 (0.1%)		3/1711 (0.2%)
Arrhythmia	1/1718 (0.1%)		0/1711 (0%)
Atrial fibrillation	2/1718 (0.1%)		3/1711 (0.2%)
Atrial flutter	1/1718 (0.1%)		0/1711 (0%)
Atrioventricular block second degree	1/1718 (0.1%)		0/1711 (0%)
Bradycardia	1/1718 (0.1%)		0/1711 (0%)
Cardiac arrest	0/1718 (0%)		3/1711 (0.2%)
Cardiac failure	1/1718 (0.1%)		1/1711 (0.1%)
Cardiac failure chronic	0/1718 (0%)		1/1711 (0.1%)
Cardiac failure congestive	0/1718 (0%)		2/1711 (0.1%)
Cardio-respiratory arrest	1/1718 (0.1%)		0/1711 (0%)
Myocardial infarction	0/1718 (0%)		1/1711 (0.1%)
Myocardial ischaemia	0/1718 (0%)		1/1711 (0.1%)
Pericarditis	1/1718 (0.1%)		0/1711 (0%)
Right ventricular failure	1/1718 (0.1%)		0/1711 (0%)
Sick sinus syndrome	0/1718 (0%)		1/1711 (0.1%)
Sinus arrhythmia	0/1718 (0%)		1/1711 (0.1%)
Tachycardia	1/1718 (0.1%)		0/1711 (0%)
Ventricular tachycardia	0/1718 (0%)		1/1711 (0.1%)
Tachyarrhythmia	1/1718 (0.1%)		0/1711 (0%)
Acute coronary syndrome	1/1718 (0.1%)		0/1711 (0%)
Cardiac disorder	1/1718 (0.1%)		0/1711 (0%)
Aortic valve disease	0/1718 (0%)		1/1711 (0.1%)
Congenital, familial and genetic disorders
Phimosis	0/1718 (0%)		1/1711 (0.1%)
Ear and labyrinth disorders
Ear haemorrhage	0/1718 (0%)		1/1711 (0.1%)
Vertigo	2/1718 (0.1%)		1/1711 (0.1%)
Sudden hearing loss	0/1718 (0%)		1/1711 (0.1%)
Endocrine disorders
Basedow's disease	1/1718 (0.1%)		0/1711 (0%)
Goitre	1/1718 (0.1%)		0/1711 (0%)
Eye disorders
Blepharochalasis	0/1718 (0%)		1/1711 (0.1%)
Conjunctival haemorrhage	0/1718 (0%)		2/1711 (0.1%)
Eye haemorrhage	1/1718 (0.1%)		0/1711 (0%)
Hyphaema	1/1718 (0.1%)		0/1711 (0%)
Maculopathy	1/1718 (0.1%)		0/1711 (0%)
Retinal detachment	1/1718 (0.1%)		0/1711 (0%)
Vitreous detachment	1/1718 (0.1%)		0/1711 (0%)
Vitreous haemorrhage	0/1718 (0%)		1/1711 (0.1%)
Gastrointestinal disorders
Abdominal discomfort	0/1718 (0%)		1/1711 (0.1%)
Abdominal pain	3/1718 (0.2%)		1/1711 (0.1%)
Abdominal pain upper	1/1718 (0.1%)		0/1711 (0%)
Ascites	1/1718 (0.1%)		0/1711 (0%)
Colitis ulcerative	1/1718 (0.1%)		1/1711 (0.1%)
Colonic polyp	0/1718 (0%)		2/1711 (0.1%)
Constipation	1/1718 (0.1%)		0/1711 (0%)
Crohn's disease	0/1718 (0%)		4/1711 (0.2%)
Diarrhoea	1/1718 (0.1%)		0/1711 (0%)
Duodenal ulcer	0/1718 (0%)		2/1711 (0.1%)
Food poisoning	0/1718 (0%)		1/1711 (0.1%)
Gastric ulcer perforation	0/1718 (0%)		1/1711 (0.1%)
Gastritis	1/1718 (0.1%)		1/1711 (0.1%)
Gastrointestinal haemorrhage	4/1718 (0.2%)		0/1711 (0%)
Gastrointestinal necrosis	0/1718 (0%)		1/1711 (0.1%)
Gingival bleeding	0/1718 (0%)		1/1711 (0.1%)
Haematemesis	1/1718 (0.1%)		3/1711 (0.2%)
Haematochezia	0/1718 (0%)		2/1711 (0.1%)
Haemorrhoids	0/1718 (0%)		1/1711 (0.1%)
Inguinal hernia, obstructive	0/1718 (0%)		1/1711 (0.1%)
Intestinal dilatation	1/1718 (0.1%)		0/1711 (0%)
Intestinal obstruction	2/1718 (0.1%)		1/1711 (0.1%)
Intestinal perforation	1/1718 (0.1%)		0/1711 (0%)
Large intestine perforation	1/1718 (0.1%)		1/1711 (0.1%)
Melaena	1/1718 (0.1%)		1/1711 (0.1%)
Nausea	1/1718 (0.1%)		0/1711 (0%)
Oesophageal ulcer haemorrhage	0/1718 (0%)		1/1711 (0.1%)
Oesophagitis	0/1718 (0%)		1/1711 (0.1%)
Pancreatic cyst	0/1718 (0%)		1/1711 (0.1%)
Pancreatitis	1/1718 (0.1%)		2/1711 (0.1%)
Pancreatitis acute	0/1718 (0%)		1/1711 (0.1%)
Rectal haemorrhage	5/1718 (0.3%)		4/1711 (0.2%)
Rectal polyp	1/1718 (0.1%)		0/1711 (0%)
Reflux oesophagitis	0/1718 (0%)		1/1711 (0.1%)
Retroperitoneal fibrosis	0/1718 (0%)		1/1711 (0.1%)
Small intestinal obstruction	0/1718 (0%)		1/1711 (0.1%)
Upper gastrointestinal haemorrhage	0/1718 (0%)		2/1711 (0.1%)
Vomiting	1/1718 (0.1%)		1/1711 (0.1%)
Lower gastrointestinal haemorrhage	0/1718 (0%)		1/1711 (0.1%)
Enterocutaneous fistula	2/1718 (0.1%)		0/1711 (0%)
Abdominal wall cyst	1/1718 (0.1%)		0/1711 (0%)
Haemorrhoidal haemorrhage	0/1718 (0%)		1/1711 (0.1%)
Intra-abdominal haematoma	1/1718 (0.1%)		0/1711 (0%)
Hernial eventration	0/1718 (0%)		1/1711 (0.1%)
Intestinal mass	0/1718 (0%)		1/1711 (0.1%)
Intestinal haemorrhage	0/1718 (0%)		1/1711 (0.1%)
General disorders
Chest pain	3/1718 (0.2%)		1/1711 (0.1%)
Death	2/1718 (0.1%)		1/1711 (0.1%)
Generalised oedema	1/1718 (0.1%)		0/1711 (0%)
Impaired healing	0/1718 (0%)		1/1711 (0.1%)
Malaise	1/1718 (0.1%)		1/1711 (0.1%)
Multi-organ failure	3/1718 (0.2%)		2/1711 (0.1%)
Oedema peripheral	3/1718 (0.2%)		0/1711 (0%)
Pelvic mass	0/1718 (0%)		1/1711 (0.1%)
Pyrexia	3/1718 (0.2%)		2/1711 (0.1%)
Sudden death	0/1718 (0%)		1/1711 (0.1%)
Sudden cardiac death	1/1718 (0.1%)		0/1711 (0%)
General physical health deterioration	0/1718 (0%)		1/1711 (0.1%)
Systemic inflammatory response syndrome	1/1718 (0.1%)		0/1711 (0%)
Medical device complication	0/1718 (0%)		1/1711 (0.1%)
Device occlusion	1/1718 (0.1%)		0/1711 (0%)
Hepatobiliary disorders
Acute hepatic failure	0/1718 (0%)		1/1711 (0.1%)
Biliary colic	0/1718 (0%)		1/1711 (0.1%)
Cholangitis	1/1718 (0.1%)		0/1711 (0%)
Cholecystitis	0/1718 (0%)		1/1711 (0.1%)
Cholecystitis acute	0/1718 (0%)		2/1711 (0.1%)
Cholelithiasis	1/1718 (0.1%)		0/1711 (0%)
Hepatic failure	0/1718 (0%)		1/1711 (0.1%)
Hepatic steatosis	0/1718 (0%)		1/1711 (0.1%)
Hepatitis acute	1/1718 (0.1%)		0/1711 (0%)
Jaundice cholestatic	0/1718 (0%)		1/1711 (0.1%)
Hepatic mass	1/1718 (0.1%)		0/1711 (0%)
Immune system disorders
Liver transplant rejection	0/1718 (0%)		1/1711 (0.1%)
Infections and infestations
Abscess	1/1718 (0.1%)		0/1711 (0%)
Appendicitis	0/1718 (0%)		1/1711 (0.1%)
Bacteraemia	1/1718 (0.1%)		0/1711 (0%)
Bronchitis	1/1718 (0.1%)		0/1711 (0%)
Bronchopneumonia	3/1718 (0.2%)		1/1711 (0.1%)
Cellulitis	3/1718 (0.2%)		4/1711 (0.2%)
Dengue fever	0/1718 (0%)		1/1711 (0.1%)
Diverticulitis	1/1718 (0.1%)		0/1711 (0%)
Endocarditis staphylococcal	0/1718 (0%)		1/1711 (0.1%)
Epiglottitis	0/1718 (0%)		1/1711 (0.1%)
Erysipelas	0/1718 (0%)		2/1711 (0.1%)
Escherichia sepsis	0/1718 (0%)		1/1711 (0.1%)
Gastroenteritis	0/1718 (0%)		4/1711 (0.2%)
Influenza	0/1718 (0%)		1/1711 (0.1%)
Lobar pneumonia	1/1718 (0.1%)		3/1711 (0.2%)
Lower respiratory tract infection	0/1718 (0%)		1/1711 (0.1%)
Mastitis	0/1718 (0%)		1/1711 (0.1%)
Paronychia	0/1718 (0%)		1/1711 (0.1%)
Pneumonia	5/1718 (0.3%)		10/1711 (0.6%)
Postoperative wound infection	1/1718 (0.1%)		1/1711 (0.1%)
Pulmonary tuberculosis	0/1718 (0%)		1/1711 (0.1%)
Pyelonephritis	1/1718 (0.1%)		0/1711 (0%)
Sepsis	2/1718 (0.1%)		7/1711 (0.4%)
Septic shock	1/1718 (0.1%)		4/1711 (0.2%)
Tracheobronchitis	1/1718 (0.1%)		0/1711 (0%)
Urinary tract infection	5/1718 (0.3%)		3/1711 (0.2%)
Viral infection	1/1718 (0.1%)		0/1711 (0%)
Anal abscess	0/1718 (0%)		1/1711 (0.1%)
Incision site abscess	1/1718 (0.1%)		0/1711 (0%)
Abscess limb	0/1718 (0%)		1/1711 (0.1%)
Pulmonary sepsis	0/1718 (0%)		1/1711 (0.1%)
Bacterial sepsis	0/1718 (0%)		1/1711 (0.1%)
Infective exacerbation of chronic obstructive airways disease	0/1718 (0%)		1/1711 (0.1%)
Cardiac valve vegetation	0/1718 (0%)		1/1711 (0.1%)
Cerebral toxoplasmosis	0/1718 (0%)		1/1711 (0.1%)
Infective aneurysm	1/1718 (0.1%)		0/1711 (0%)
Wound abscess	1/1718 (0.1%)		0/1711 (0%)
Abdominal abscess	0/1718 (0%)		2/1711 (0.1%)
Pneumonia bacterial	0/1718 (0%)		2/1711 (0.1%)
Lung infection	0/1718 (0%)		1/1711 (0.1%)
Respiratory tract infection	1/1718 (0.1%)		2/1711 (0.1%)
Device related infection	0/1718 (0%)		1/1711 (0.1%)
Incision site infection	0/1718 (0%)		1/1711 (0.1%)
Post procedural sepsis	0/1718 (0%)		1/1711 (0.1%)
Injury, poisoning and procedural complications
Accident	0/1718 (0%)		1/1711 (0.1%)
Alcohol poisoning	0/1718 (0%)		1/1711 (0.1%)
Ankle fracture	0/1718 (0%)		1/1711 (0.1%)
Cartilage injury	0/1718 (0%)		1/1711 (0.1%)
Clavicle fracture	1/1718 (0.1%)		0/1711 (0%)
Drug toxicity	1/1718 (0.1%)		0/1711 (0%)
Femoral neck fracture	0/1718 (0%)		2/1711 (0.1%)
Femur fracture	0/1718 (0%)		1/1711 (0.1%)
Humerus fracture	2/1718 (0.1%)		0/1711 (0%)
Joint dislocation	0/1718 (0%)		1/1711 (0.1%)
Overdose	1/1718 (0.1%)		1/1711 (0.1%)
Pneumothorax traumatic	0/1718 (0%)		1/1711 (0.1%)
Radiation pneumonitis	0/1718 (0%)		1/1711 (0.1%)
Radius fracture	0/1718 (0%)		1/1711 (0.1%)
Rib fracture	1/1718 (0.1%)		0/1711 (0%)
Spinal compression fracture	1/1718 (0.1%)		1/1711 (0.1%)
Subdural haematoma	0/1718 (0%)		1/1711 (0.1%)
Therapeutic agent toxicity	0/1718 (0%)		2/1711 (0.1%)
Ulna fracture	0/1718 (0%)		1/1711 (0.1%)
Wound dehiscence	1/1718 (0.1%)		0/1711 (0%)
Vascular pseudoaneurysm	1/1718 (0.1%)		0/1711 (0%)
Thoracic vertebral fracture	0/1718 (0%)		1/1711 (0.1%)
Contusion	2/1718 (0.1%)		1/1711 (0.1%)
Post procedural haemorrhage	1/1718 (0.1%)		2/1711 (0.1%)
Induced abortion haemorrhage	1/1718 (0.1%)		0/1711 (0%)
Traumatic haemorrhage	1/1718 (0.1%)		0/1711 (0%)
Skin laceration	1/1718 (0.1%)		1/1711 (0.1%)
Gastrointestinal disorder postoperative	1/1718 (0.1%)		0/1711 (0%)
Ligament injury	0/1718 (0%)		1/1711 (0.1%)
Post procedural haematuria	1/1718 (0.1%)		0/1711 (0%)
Investigations
Alanine aminotransferase increased	2/1718 (0.1%)		6/1711 (0.4%)
Blood bilirubin increased	1/1718 (0.1%)		0/1711 (0%)
Chest X-ray abnormal	0/1718 (0%)		1/1711 (0.1%)
International normalised ratio increased	0/1718 (0%)		5/1711 (0.3%)
Liver function test abnormal	2/1718 (0.1%)		4/1711 (0.2%)
Weight decreased	1/1718 (0.1%)		0/1711 (0%)
Transaminases increased	2/1718 (0.1%)		0/1711 (0%)
Hepatic enzyme increased	1/1718 (0.1%)		5/1711 (0.3%)
International normalised ratio fluctuation	0/1718 (0%)		1/1711 (0.1%)
Metabolism and nutrition disorders
Dehydration	0/1718 (0%)		1/1711 (0.1%)
Diabetes mellitus inadequate control	1/1718 (0.1%)		0/1711 (0%)
Diabetic ketoacidosis	1/1718 (0.1%)		0/1711 (0%)
Hypoglycaemia	0/1718 (0%)		1/1711 (0.1%)
Hypokalaemia	1/1718 (0.1%)		0/1711 (0%)
Hypoproteinaemia	1/1718 (0.1%)		0/1711 (0%)
Tetany	1/1718 (0.1%)		0/1711 (0%)
Metabolic disorder	0/1718 (0%)		1/1711 (0.1%)
Diabetic foot	0/1718 (0%)		1/1711 (0.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/1718 (0.1%)		0/1711 (0%)
Arthritis	0/1718 (0%)		2/1711 (0.1%)
Back pain	3/1718 (0.2%)		2/1711 (0.1%)
Bursitis	1/1718 (0.1%)		0/1711 (0%)
Haemarthrosis	0/1718 (0%)		2/1711 (0.1%)
Muscle haemorrhage	0/1718 (0%)		3/1711 (0.2%)
Musculoskeletal pain	1/1718 (0.1%)		0/1711 (0%)
Myalgia	1/1718 (0.1%)		0/1711 (0%)
Osteoarthritis	1/1718 (0.1%)		0/1711 (0%)
Osteoporosis	1/1718 (0.1%)		0/1711 (0%)
Pain in extremity	0/1718 (0%)		1/1711 (0.1%)
Pathological fracture	1/1718 (0.1%)		0/1711 (0%)
Rotator cuff syndrome	0/1718 (0%)		1/1711 (0.1%)
Synovitis	0/1718 (0%)		1/1711 (0.1%)
Systemic lupus erythematosus	1/1718 (0.1%)		0/1711 (0%)
Joint range of motion decreased	1/1718 (0.1%)		0/1711 (0%)
Intervertebral disc protrusion	1/1718 (0.1%)		1/1711 (0.1%)
Musculoskeletal chest pain	0/1718 (0%)		1/1711 (0.1%)
Juvenile arthritis	0/1718 (0%)		1/1711 (0.1%)
Foot deformity	0/1718 (0%)		1/1711 (0.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute leukaemia	0/1718 (0%)		1/1711 (0.1%)
Angiosarcoma	1/1718 (0.1%)		0/1711 (0%)
Basal cell carcinoma	0/1718 (0%)		1/1711 (0.1%)
Bile duct cancer	1/1718 (0.1%)		0/1711 (0%)
Bladder cancer	2/1718 (0.1%)		0/1711 (0%)
Breast cancer	3/1718 (0.2%)		1/1711 (0.1%)
Cervix carcinoma	2/1718 (0.1%)		7/1711 (0.4%)
Cervix carcinoma stage III	1/1718 (0.1%)		0/1711 (0%)
Colon cancer	2/1718 (0.1%)		4/1711 (0.2%)
Endometrial cancer	1/1718 (0.1%)		1/1711 (0.1%)
Gastric cancer	1/1718 (0.1%)		1/1711 (0.1%)
Gastric cancer recurrent	1/1718 (0.1%)		0/1711 (0%)
Hepatic neoplasm malignant	2/1718 (0.1%)		2/1711 (0.1%)
Large cell carcinoma of the respiratory tract stage unspecified	0/1718 (0%)		1/1711 (0.1%)
Lung adenocarcinoma	0/1718 (0%)		3/1711 (0.2%)
Lung carcinoma cell type unspecified recurrent	1/1718 (0.1%)		0/1711 (0%)
Lymphoma	3/1718 (0.2%)		0/1711 (0%)
Malignant melanoma	1/1718 (0.1%)		0/1711 (0%)
Meningioma	0/1718 (0%)		1/1711 (0.1%)
Metastases to liver	2/1718 (0.1%)		4/1711 (0.2%)
Metastases to lung	1/1718 (0.1%)		2/1711 (0.1%)
Metastases to lymph nodes	2/1718 (0.1%)		1/1711 (0.1%)
Non-Hodgkin's lymphoma	2/1718 (0.1%)		0/1711 (0%)
Oesophageal adenocarcinoma	1/1718 (0.1%)		0/1711 (0%)
Oesophageal carcinoma	0/1718 (0%)		1/1711 (0.1%)
Ovarian cancer	2/1718 (0.1%)		2/1711 (0.1%)
Pancreatic carcinoma	3/1718 (0.2%)		0/1711 (0%)
Pancreatic carcinoma metastatic	0/1718 (0%)		2/1711 (0.1%)
Prostate cancer metastatic	0/1718 (0%)		1/1711 (0.1%)
Rectal cancer	1/1718 (0.1%)		2/1711 (0.1%)
Rectal cancer recurrent	1/1718 (0.1%)		0/1711 (0%)
Renal cell carcinoma recurrent	0/1718 (0%)		1/1711 (0.1%)
Rhabdomyosarcoma	1/1718 (0.1%)		0/1711 (0%)
Uterine cancer	0/1718 (0%)		1/1711 (0.1%)
Uterine leiomyoma	1/1718 (0.1%)		0/1711 (0%)
Waldenstrom's macroglobulinaemia	1/1718 (0.1%)		0/1711 (0%)
Lung cancer metastatic	1/1718 (0.1%)		0/1711 (0%)
Metastases to peritoneum	1/1718 (0.1%)		0/1711 (0%)
Lymphoma cutis	1/1718 (0.1%)		0/1711 (0%)
Ear neoplasm malignant	0/1718 (0%)		1/1711 (0.1%)
Cervix cancer metastatic	1/1718 (0.1%)		0/1711 (0%)
Hepatic cancer metastatic	1/1718 (0.1%)		0/1711 (0%)
Breast cancer metastatic	1/1718 (0.1%)		0/1711 (0%)
Retroperitoneal neoplasm	0/1718 (0%)		1/1711 (0.1%)
Ovarian cancer metastatic	0/1718 (0%)		1/1711 (0.1%)
Lung neoplasm malignant	2/1718 (0.1%)		3/1711 (0.2%)
Large intestine carcinoma	1/1718 (0.1%)		0/1711 (0%)
Metastases to central nervous system	1/1718 (0.1%)		1/1711 (0.1%)
Small cell lung cancer metastatic	1/1718 (0.1%)		0/1711 (0%)
Prostate cancer	1/1718 (0.1%)		1/1711 (0.1%)
Metastatic neoplasm	2/1718 (0.1%)		1/1711 (0.1%)
Ovarian epithelial cancer	0/1718 (0%)		1/1711 (0.1%)
Pelvic neoplasm	1/1718 (0.1%)		0/1711 (0%)
Colorectal cancer	2/1718 (0.1%)		0/1711 (0%)
Renal neoplasm	0/1718 (0%)		1/1711 (0.1%)
Non-small cell lung cancer	0/1718 (0%)		1/1711 (0.1%)
Lung neoplasm	2/1718 (0.1%)		1/1711 (0.1%)
Penis carcinoma	0/1718 (0%)		1/1711 (0.1%)
Metastatic squamous cell carcinoma	0/1718 (0%)		1/1711 (0.1%)
Ovarian cancer recurrent	0/1718 (0%)		1/1711 (0.1%)
Bladder transitional cell carcinoma stage I	0/1718 (0%)		1/1711 (0.1%)
Renal cell carcinoma	1/1718 (0.1%)		0/1711 (0%)
Nervous system disorders
Cerebral haemorrhage	1/1718 (0.1%)		1/1711 (0.1%)
Dizziness	0/1718 (0%)		2/1711 (0.1%)
Epilepsy	1/1718 (0.1%)		1/1711 (0.1%)
Facial palsy	1/1718 (0.1%)		0/1711 (0%)
Grand mal convulsion	1/1718 (0.1%)		0/1711 (0%)
Haemorrhage intracranial	1/1718 (0.1%)		1/1711 (0.1%)
Headache	1/1718 (0.1%)		1/1711 (0.1%)
Hypoglycaemic coma	1/1718 (0.1%)		0/1711 (0%)
Migraine	1/1718 (0.1%)		0/1711 (0%)
Mononeuritis	1/1718 (0.1%)		0/1711 (0%)
Multiple sclerosis	1/1718 (0.1%)		0/1711 (0%)
Neuralgia	0/1718 (0%)		1/1711 (0.1%)
Presyncope	1/1718 (0.1%)		0/1711 (0%)
Syncope	1/1718 (0.1%)		2/1711 (0.1%)
Transient ischaemic attack	1/1718 (0.1%)		4/1711 (0.2%)
IIIrd nerve paresis	0/1718 (0%)		1/1711 (0.1%)
Cognitive disorder	1/1718 (0.1%)		0/1711 (0%)
Ischaemic stroke	4/1718 (0.2%)		7/1711 (0.4%)
Parkinson's disease	1/1718 (0.1%)		0/1711 (0%)
Metabolic encephalopathy	1/1718 (0.1%)		0/1711 (0%)
Complex regional pain syndrome	0/1718 (0%)		1/1711 (0.1%)
Cerebral arteriosclerosis	1/1718 (0.1%)		0/1711 (0%)
Pregnancy, puerperium and perinatal conditions
Abortion	0/1718 (0%)		1/1711 (0.1%)
Post abortion haemorrhage	0/1718 (0%)		1/1711 (0.1%)
Psychiatric disorders
Acute psychosis	0/1718 (0%)		1/1711 (0.1%)
Alcohol abuse	0/1718 (0%)		1/1711 (0.1%)
Completed suicide	0/1718 (0%)		1/1711 (0.1%)
Confusional state	0/1718 (0%)		1/1711 (0.1%)
Depression	3/1718 (0.2%)		2/1711 (0.1%)
Panic attack	1/1718 (0.1%)		1/1711 (0.1%)
Suicide attempt	1/1718 (0.1%)		0/1711 (0%)
Major depression	1/1718 (0.1%)		0/1711 (0%)
Psychotic disorder	1/1718 (0.1%)		0/1711 (0%)
Renal and urinary disorders
Anuria	1/1718 (0.1%)		0/1711 (0%)
Calculus ureteric	1/1718 (0.1%)		0/1711 (0%)
Cystitis haemorrhagic	1/1718 (0.1%)		0/1711 (0%)
Haematuria	4/1718 (0.2%)		8/1711 (0.5%)
Hydronephrosis	0/1718 (0%)		2/1711 (0.1%)
Nephrolithiasis	0/1718 (0%)		1/1711 (0.1%)
Nephrotic syndrome	1/1718 (0.1%)		0/1711 (0%)
Renal colic	0/1718 (0%)		1/1711 (0.1%)
Renal failure	1/1718 (0.1%)		0/1711 (0%)
Renal failure acute	1/1718 (0.1%)		3/1711 (0.2%)
Reproductive system and breast disorders
Menorrhagia	5/1718 (0.3%)		1/1711 (0.1%)
Ovarian cyst	1/1718 (0.1%)		1/1711 (0.1%)
Pelvic pain	0/1718 (0%)		1/1711 (0.1%)
Penile swelling	0/1718 (0%)		1/1711 (0.1%)
Prostatitis	1/1718 (0.1%)		0/1711 (0%)
Scrotal swelling	0/1718 (0%)		1/1711 (0.1%)
Uterine polyp	1/1718 (0.1%)		0/1711 (0%)
Vaginal haemorrhage	3/1718 (0.2%)		2/1711 (0.1%)
Postmenopausal haemorrhage	1/1718 (0.1%)		0/1711 (0%)
Haemorrhagic ovarian cyst	1/1718 (0.1%)		0/1711 (0%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/1718 (0.1%)		3/1711 (0.2%)
Chronic obstructive pulmonary disease	4/1718 (0.2%)		2/1711 (0.1%)
Cough	2/1718 (0.1%)		0/1711 (0%)
Dyspnoea	2/1718 (0.1%)		5/1711 (0.3%)
Dyspnoea at rest	1/1718 (0.1%)		0/1711 (0%)
Epistaxis	1/1718 (0.1%)		1/1711 (0.1%)
Haemoptysis	1/1718 (0.1%)		2/1711 (0.1%)
Haemothorax	0/1718 (0%)		1/1711 (0.1%)
Interstitial lung disease	0/1718 (0%)		1/1711 (0.1%)
Lung disorder	1/1718 (0.1%)		0/1711 (0%)
Pleural effusion	1/1718 (0.1%)		1/1711 (0.1%)
Pulmonary embolism	1/1718 (0.1%)		2/1711 (0.1%)
Pulmonary fibrosis	1/1718 (0.1%)		0/1711 (0%)
Pulmonary oedema	0/1718 (0%)		1/1711 (0.1%)
Respiratory distress	0/1718 (0%)		1/1711 (0.1%)
Respiratory failure	1/1718 (0.1%)		1/1711 (0.1%)
Tachypnoea	0/1718 (0%)		1/1711 (0.1%)
Wegener's granulomatosis	1/1718 (0.1%)		0/1711 (0%)
Pulmonary mass	1/1718 (0.1%)		0/1711 (0%)
Sputum retention	1/1718 (0.1%)		0/1711 (0%)
Skin and subcutaneous tissue disorders
Dermatitis exfoliative	0/1718 (0%)		1/1711 (0.1%)
Drug eruption	0/1718 (0%)		1/1711 (0.1%)
Henoch-Schonlein purpura	0/1718 (0%)		1/1711 (0.1%)
Leukocytoclastic vasculitis	0/1718 (0%)		1/1711 (0.1%)
Scar	0/1718 (0%)		1/1711 (0.1%)
Skin ulcer	0/1718 (0%)		1/1711 (0.1%)
Surgical and medical procedures
Abortion induced	0/1718 (0%)		1/1711 (0.1%)
Bladder catheter removal	1/1718 (0.1%)		0/1711 (0%)
Uterine polypectomy	0/1718 (0%)		1/1711 (0.1%)
Ileostomy closure	1/1718 (0.1%)		0/1711 (0%)
Vascular disorders
Aortic aneurysm	0/1718 (0%)		1/1711 (0.1%)
Arterial thrombosis limb	1/1718 (0.1%)		1/1711 (0.1%)
Arteriosclerosis	0/1718 (0%)		2/1711 (0.1%)
Circulatory collapse	1/1718 (0.1%)		0/1711 (0%)
Haematoma	1/1718 (0.1%)		4/1711 (0.2%)
Hypertension	2/1718 (0.1%)		0/1711 (0%)
Hypertensive crisis	0/1718 (0%)		1/1711 (0.1%)
Hypotension	0/1718 (0%)		1/1711 (0.1%)
Jugular vein thrombosis	0/1718 (0%)		1/1711 (0.1%)
Lymphoedema	1/1718 (0.1%)		0/1711 (0%)
Peripheral ischaemia	1/1718 (0.1%)		2/1711 (0.1%)
Peripheral vascular disorder	0/1718 (0%)		1/1711 (0.1%)
Shock	0/1718 (0%)		1/1711 (0.1%)
Thrombophlebitis superficial	0/1718 (0%)		1/1711 (0.1%)
Thrombosis	0/1718 (0%)		1/1711 (0.1%)
Post thrombotic syndrome	0/1718 (0%)		1/1711 (0.1%)
Shock haemorrhagic	0/1718 (0%)		1/1711 (0.1%)
Femoral artery occlusion	1/1718 (0.1%)		0/1711 (0%)
Iliac artery stenosis	0/1718 (0%)		1/1711 (0.1%)
Peripheral artery aneurysm	1/1718 (0.1%)		0/1711 (0%)
Extremity necrosis	0/1718 (0%)		1/1711 (0.1%)
Arterial haemorrhage	0/1718 (0%)		1/1711 (0.1%)
Peripheral embolism	0/1718 (0%)		1/1711 (0.1%)
Peripheral arterial occlusive disease	2/1718 (0.1%)		0/1711 (0%)
May-Thurner syndrome	0/1718 (0%)		1/1711 (0.1%)
Other (Not Including Serious) Adverse Events
	Rivaroxaban (Xarelto, BAY59-7939)		Enoxaparin/VKA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	241/1718 (14%)		212/1711 (12.4%)
Infections and infestations
Nasopharyngitis	100/1718 (5.8%)		91/1711 (5.3%)
Nervous system disorders
Headache	91/1718 (5.3%)		70/1711 (4.1%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	90/1718 (5.2%)		74/1711 (4.3%)

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.