Venous Thromboembolism
Conditions
Keywords
Acute medical illnesses with increased risk for VTE., Deep vein thrombosis (DVT), Pulmonary embolism (PE),, Venous Thromboembolic disease (VTE),, Medical illness
Brief summary
This study will evaluate if extended therapy with oral rivaroxaban can prevent blood clots in the leg and lung that can occur with patients hospitalized for acute medical illness, and compare these results with those of the standard enoxaparin dose and duration regimen. The safety of rivaroxaban will also be studied.
Detailed description
The treatment period was followed by a follow-up period starting the day after the last intake of study medication, regardless of the actual duration of study drug administration and ended on Day 90 (+ 7 days). Participants who did not complete the treatment period also entered the follow-up period. It was also possible that participants did not enter the follow-up period, e.g. due to withdrawal of consent or termination of study participation. Within the US 'Johnson & Johnson Pharmaceutical Research & Development, L.L.C.' is sponsor.
Interventions
DRUGRivaroxaban (Xarelto, BAY59-7939)
Oral rivaroxaban 10 mg once daily administered for 35 +/- 4 days
DRUGEnoxaparin
Subcutaneous enoxaparin 40 mg once daily (OD) administered for 10 +/- 4 days
Oral rivaroxaban-matched placebo tablet OD for 35 +/- 4 days
Subcutaneous enoxaparin-matched placebo solution OD for 10 +/- 4 days
Sponsors
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female patients aged 40 years or more * Patients at risk of venous thromboembolic events being hospitalized for acute medical conditions as follows: * Heart failure, New York Heart Association (NYHA) class III or IV * Active cancer * Acute ischemic stroke * Acute infectious and inflammatory diseases, including acute rheumatic diseases * Acute respiratory insufficiency * Additional risk factor for VTE, including reduced mobility
Exclusion criteria
* Conditions that contraindicate the use of antithrombotic therapy with the Low Molecular-Weight Heparin (LMWH) enoxaparin * Conditions that may increase the risk of bleeding, including intracranial hemorrhage * Required drugs or procedures which may interfere with the study treatment * Concomitant conditions or diseases which may increase the risk of study subjects or interfere with the study outcome * General conditions in which subjects are not suitable to participate in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Composite Endpoint of Venous Thromboembolism [VTE] (Any Deep Vein Thrombosis [DVT], Non Fatal Pulmonary Embolism [PE]) and VTE-related Death up to Day 35 + 6 Days | Up to Day 35 + 6 days | A composite endpoint of: asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and VTE-related death. |
| Percentage of Participants With Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 10 + 5 Days | Up to Day 10 + 5 days | A composite endpoint of: asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and VTE-related death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 10 + 5 Days Per mITT Population | Up to Day 10 + 5 days | A composite endpoint of: asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and VTE-related death. |
| Percentage of Participants With Symptomatic VTE, Including and Excluding VTE-related Death up to Days 10, 35, and 90 | At Day 10 + 5 days, at Day 35 + 6 days, and at Day 90 + 7 days | Symptomatic VTE (non-fatal PE and DVT in lower extremity), including and excluding VTE-related death (PE and PE cannot be excluded) up to Days 10, 35, and 90 |
| Percentage of Participants With Net Clinical Benefit (Any DVT, Non-fatal PE, VTE-related Death, Plus Major and Clinically Relevant Non-major Bleeding Events) up to Day 35 + 6 Days | Up to Day 35 + 6 days | Net clinical benefit is a composite of the primary efficacy endpoint (asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and VTE-related death) plus major and clinically relevant non-major bleeding events. |
| Percentage of Participants With Net Clinical Benefit (Any DVT, Non-fatal PE, VTE-related Death, Plus Major and Clinically Relevant Non-major Bleeding Events) up to Day 10 + 5 Days | Up to Day 10 + 5 days | Net clinical benefit is a composite of the primary efficacy endpoint (asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and VTE-related death) plus major and clinically relevant non-major bleeding events |
| Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | At Day 10 + 5 days, at Day 35 + 6 days, and at Day 90 + 7 days | Major vascular events included cardiovascular death, acute myocardial infarction (MI), or acute ischemic stroke. Participants may have had a vascular event in more than one category. |
| Percentage of Participants With VTE Combined With All-cause Mortality up to Day 10 + 5 Days | Up to Day 10 + 5 days | A composite endpoint of: asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and death (VTE-related and not VTE-related). |
| Percentage of Participants With Each Component of the Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 10 + 5 Days | Up to Day 10 + 5 days | The components of the composite endpoint include asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and VTE-related death. |
| Percentage of Participants With All-cause Mortality up to Day 90 + 7 Days | Up to Day 90 + 7 days | All deaths, including VTE-related deaths, cardiovascular deaths, and other deaths. |
| Percentage of Participants With the Composite of Treatment Emergent Major Bleeding Events and Non-major Clinically Relevant Bleeding Events up to 2 Days After Last Intake of Any Study Medication (Day 35 + 6 Days) | Up to Day 35 + 6 days | Major bleeding events were defined as events leading to \>=2 g/dL fall in hemoglobin; or transfusion of \>= 2 units of packed RBCs (Red blood cells) or whole blood; or leading to death. Non-major bleeding events were defined as overt bleeding not meeting the criteria of major bleeding |
| Percentage of Participants With the Composite of Treatment Emergent Major Bleeding Events and Non-major Clinically Relevant Bleeding Events up to 2 Days After Last Application of a Study Medication Syringe (Day 10 + 5 Days) | Up to Day 10 + 5 days | Major bleeding events were defined as events leading to \>=2 g/dL fall in hemoglobin or transfusion of \>=2 units of packed RBCs or whole blood or leading to death. Non-major bleeding events were defined as overt bleeding not meeting the criteria of major bleeding. |
| Percentage of Participants With Each Component of the Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 35 + 6 Days | Up to Day 35 + 6 days | The components of the composite endpoint include asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and VTE-related death. |
| Percentage of Participants With Composite Endpoint of VTE (Any DVT, Non Fatal PE) and All-cause Mortality up to Day 35 + 6 Days | Up to Day 35 + 6 days | A composite endpoint of: asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and death (VTE-related and not VTE-related). |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Croatia, Czechia, Denmark, Estonia, Finland, France, Germany, Greece, Hong Kong, Hungary, India, Indonesia, Israel, Italy, Japan, Latvia, Lithuania, Luxembourg, Malaysia, Mexico, Netherlands, New Zealand, Norway, Pakistan, Peru, Poland, Portugal, Romania, Russia, Singapore, Slovakia, Slovenia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
First patient first visit date: 04 DEC 2007; last patient last visit date 24 NOV 2010. Primary completion date: 12 AUG 2010. Participants were aged ≥40 years, hospitalized for an acute medical illness, and at risk of Venous Thromboembolism (VTE) (with heart failure, cancer, ischemic stroke, infection or inflammation, or respiratory insufficiency)
Pre-assignment details
A total of 8428 participants were screened; 327 failed. 8101 were randomized. 7998 (98.7%) were in the Safety Analysis Set (SAF), i.e. received study medication. 6024 (74.4%) were in the modified Intent to Treat (at Day 35) group (valid for SAF with adequate assessment of venous thromboembolism). A total of 6005 (74.1%) completed study.
Participants by arm
| Arm | Count |
|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) Participants received 10 mg oral rivaroxaban tablet once daily (OD) for 35 +/- 4 days, plus subcutaneous enoxaparin-matched placebo solution OD for 10 +/- 4 days (SAF population) | 3,997 |
| Enoxaparin Participants received oral rivaroxaban-matched placebo tablet OD for 35 +/- 4 days, plus 40 mg subcutaneous enoxaparin solution OD for 10 +/- 4 days (SAF population) | 4,001 |
| Total | 7,998 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Follow-up Period | Adverse Event | 46 | 40 |
| Follow-up Period | Clinical endpoint reached | 5 | 2 |
| Follow-up Period | Death | 132 | 133 |
| Follow-up Period | Lost to Follow-up | 95 | 92 |
| Follow-up Period | Patient convenience | 136 | 121 |
| Follow-up Period | Physician Decision | 7 | 13 |
| Follow-up Period | Protocol Violation | 5 | 12 |
| Follow-up Period | Withdrawal by Subject | 119 | 115 |
| Treatment Period | Adverse Event | 438 | 385 |
| Treatment Period | Clinical endpoint reached | 50 | 56 |
| Treatment Period | Death | 76 | 59 |
| Treatment Period | Lost to Follow-up | 43 | 41 |
| Treatment Period | Non-compliant with study medication | 88 | 89 |
| Treatment Period | Patient convenience | 11 | 13 |
| Treatment Period | Physician Decision | 8 | 9 |
| Treatment Period | Protocol Violation | 90 | 92 |
| Treatment Period | Technical problems | 3 | 5 |
| Treatment Period | Withdrawal by Subject | 285 | 255 |
Baseline characteristics
| Characteristic | Enoxaparin | Total | Rivaroxaban (Xarelto, BAY59-7939) |
|---|---|---|---|
| Age, Continuous | 69.2 years STANDARD_DEVIATION 11.7 | 69.2 years STANDARD_DEVIATION 11.8 | 69.2 years STANDARD_DEVIATION 11.9 |
| Age, Customized 65 to < 75 years | 1090 participants | 2234 participants | 1144 participants |
| Age, Customized < 65 years | 1363 participants | 2686 participants | 1323 participants |
| Age, Customized >= 75 years | 1548 participants | 3078 participants | 1530 participants |
| Race Asian | 794 participants | 1587 participants | 793 participants |
| Race Black | 92 participants | 181 participants | 89 participants |
| Race Hispanic | 70 participants | 139 participants | 69 participants |
| Race Missing | 177 participants | 355 participants | 178 participants |
| Race Native American | 12 participants | 24 participants | 12 participants |
| Race Uncodable | 112 participants | 218 participants | 106 participants |
| Race Unknown | 0 participants | 1 participants | 1 participants |
| Race White | 2744 participants | 5493 participants | 2749 participants |
| Reason for hospitalization Active cancer | 290 participants | 584 participants | 294 participants |
| Reason for hospitalization Acute Infectious and Inflammatory Diseases | 1876 participants | 3780 participants | 1904 participants |
| Reason for hospitalization Acute infectious disease | 1801 participants | 3627 participants | 1826 participants |
| Reason for hospitalization Acute inflammatory or rheumatic disease | 149 participants | 299 participants | 150 participants |
| Reason for hospitalization Acute ischemic stroke | 692 participants | 1383 participants | 691 participants |
| Reason for hospitalization Acute respiratory insufficiency | 1151 participants | 2236 participants | 1085 participants |
| Reason for hospitalization Heart failure (NYHA Class III or NYHA Class IV) | 1301 participants | 2593 participants | 1292 participants |
| Sex: Female, Male Female | 1898 Participants | 3672 Participants | 1774 Participants |
| Sex: Female, Male Male | 2103 Participants | 4326 Participants | 2223 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2,297 / 3,997 | 2,291 / 4,001 |
| serious Total, serious adverse events | 1,034 / 3,997 | 976 / 4,001 |
Outcome results
Primary
Percentage of Participants With Composite Endpoint of Venous Thromboembolism [VTE] (Any Deep Vein Thrombosis [DVT], Non Fatal Pulmonary Embolism [PE]) and VTE-related Death up to Day 35 + 6 Days
A composite endpoint of: asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and VTE-related death.
Time frame: Up to Day 35 + 6 days
Population: modified Intent-to-Treat (mITT) Day 35: participant was valid for the safety analysis and had an adequate assessment of VTE up to Day 35
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Composite Endpoint of Venous Thromboembolism [VTE] (Any Deep Vein Thrombosis [DVT], Non Fatal Pulmonary Embolism [PE]) and VTE-related Death up to Day 35 + 6 Days | 4.4 Percentage of participants |
| Enoxaparin | Percentage of Participants With Composite Endpoint of Venous Thromboembolism [VTE] (Any Deep Vein Thrombosis [DVT], Non Fatal Pulmonary Embolism [PE]) and VTE-related Death up to Day 35 + 6 Days | 5.7 Percentage of participants |
Comparison: A sample size of 2876 valid patients per group was estimated to obtain a joint power of at least 90% for both primary endpoints (91.4% for superiority) with 4% event rate at day 35 for comparator and 40% relative risk reduction.p-value: 0.021195% CI: [0.618, 0.962]Cochran-Mantel-Haenszel
Primary
Percentage of Participants With Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 10 + 5 Days
A composite endpoint of: asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and VTE-related death.
Time frame: Up to Day 10 + 5 days
Population: Per Protocol (PP) Day 10: participant was valid for the safety analysis, had an adequate assessment of VTE up to Day 10 not later than 48 hours after stop of study drug, met inclusion criteria, and had no major protocol deviations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 10 + 5 Days | 2.7 Percentage of participants |
| Enoxaparin | Percentage of Participants With Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 10 + 5 Days | 2.7 Percentage of participants |
Comparison: A sample size of 2876 valid patients per group was estimated to obtain a joint power of at least 90% for both primary endpoints (98.6% power for non-inferiority) with 1.8% event rate at day 10 for comparator and 35% relative risk reduction.p-value: 0.002595% CI: [0.713, 1.314]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With All-cause Mortality up to Day 90 + 7 Days
All deaths, including VTE-related deaths, cardiovascular deaths, and other deaths.
Time frame: Up to Day 90 + 7 days
Population: Safety population: Participant had at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With All-cause Mortality up to Day 90 + 7 Days | Any event | 6.7 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With All-cause Mortality up to Day 90 + 7 Days | Death (cardiovascular) | 1.4 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With All-cause Mortality up to Day 90 + 7 Days | Death (other) | 4.3 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With All-cause Mortality up to Day 90 + 7 Days | VTE related death | 1.0 Percentage of participants |
| Enoxaparin | Percentage of Participants With All-cause Mortality up to Day 90 + 7 Days | VTE related death | 1.1 Percentage of participants |
| Enoxaparin | Percentage of Participants With All-cause Mortality up to Day 90 + 7 Days | Any event | 6.2 Percentage of participants |
| Enoxaparin | Percentage of Participants With All-cause Mortality up to Day 90 + 7 Days | Death (other) | 3.7 Percentage of participants |
| Enoxaparin | Percentage of Participants With All-cause Mortality up to Day 90 + 7 Days | Death (cardiovascular) | 1.4 Percentage of participants |
Secondary
Percentage of Participants With Composite Endpoint of VTE (Any DVT, Non Fatal PE) and All-cause Mortality up to Day 35 + 6 Days
A composite endpoint of: asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and death (VTE-related and not VTE-related).
Time frame: Up to Day 35 + 6 days
Population: modified Intent-to-Treat (mITT) Day 35 (participant was valid for the safety analysis and had an adequate assessment of VTE up to Day 35) expanded to include participants who had an assessment of all deaths, including not VTE-related
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Composite Endpoint of VTE (Any DVT, Non Fatal PE) and All-cause Mortality up to Day 35 + 6 Days | 8.6 Percentage of participants |
| Enoxaparin | Percentage of Participants With Composite Endpoint of VTE (Any DVT, Non Fatal PE) and All-cause Mortality up to Day 35 + 6 Days | 9.2 Percentage of participants |
p-value: 0.375895% CI: [0.795, 1.091]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 10 + 5 Days Per mITT Population
A composite endpoint of: asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and VTE-related death.
Time frame: Up to Day 10 + 5 days
Population: modified Intent-to-Treat (mITT) Day 10: participant was valid for the safety analysis and had an adequate assessment of VTE up to Day 10
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 10 + 5 Days Per mITT Population | 3.0 Percentage of participants |
| Enoxaparin | Percentage of Participants With Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 10 + 5 Days Per mITT Population | 3.1 Percentage of participants |
p-value: 0.947395% CI: [0.753, 1.304]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Each Component of the Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 10 + 5 Days
The components of the composite endpoint include asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and VTE-related death.
Time frame: Up to Day 10 + 5 days
Population: Per Protocol Day 10: participant was valid for the safety analysis, had an adequate assessment of VTE up to Day 10 not later than 48 hours after stop of study drug, met inclusion criteria, and had no major protocol deviations
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Each Component of the Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 10 + 5 Days | Symptomatic non-fatal PE | 0.2 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Each Component of the Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 10 + 5 Days | Symptomatic DVT in lower extremity | 0.2 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Each Component of the Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 10 + 5 Days | Asymptomatic proximal DVT in lower extremity | 2.4 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Each Component of the Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 10 + 5 Days | VTE related death | 0.1 Percentage of participants |
| Enoxaparin | Percentage of Participants With Each Component of the Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 10 + 5 Days | VTE related death | 0.2 Percentage of participants |
| Enoxaparin | Percentage of Participants With Each Component of the Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 10 + 5 Days | Symptomatic non-fatal PE | 0.1 Percentage of participants |
| Enoxaparin | Percentage of Participants With Each Component of the Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 10 + 5 Days | Asymptomatic proximal DVT in lower extremity | 2.4 Percentage of participants |
| Enoxaparin | Percentage of Participants With Each Component of the Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 10 + 5 Days | Symptomatic DVT in lower extremity | 0.2 Percentage of participants |
Secondary
Percentage of Participants With Each Component of the Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 35 + 6 Days
The components of the composite endpoint include asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and VTE-related death.
Time frame: Up to Day 35 + 6 days
Population: modified Intent-to-Treat (mITT) Day 35: participant was valid for the safety analysis and had an adequate assessment of VTE up to Day 35
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Each Component of the Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 35 + 6 Days | Symptomatic non-fatal PE | 0.3 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Each Component of the Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 35 + 6 Days | Symptomatic DVT in lower extremity | 0.4 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Each Component of the Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 35 + 6 Days | Asymptomatic proximal DVT in lower extremity | 3.5 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Each Component of the Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 35 + 6 Days | VTE related death | 0.6 Percentage of participants |
| Enoxaparin | Percentage of Participants With Each Component of the Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 35 + 6 Days | VTE related death | 1.0 Percentage of participants |
| Enoxaparin | Percentage of Participants With Each Component of the Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 35 + 6 Days | Symptomatic non-fatal PE | 0.5 Percentage of participants |
| Enoxaparin | Percentage of Participants With Each Component of the Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 35 + 6 Days | Asymptomatic proximal DVT in lower extremity | 4.4 Percentage of participants |
| Enoxaparin | Percentage of Participants With Each Component of the Composite Endpoint of VTE (Any DVT, Non Fatal PE) and VTE-related Death up to Day 35 + 6 Days | Symptomatic DVT in lower extremity | 0.5 Percentage of participants |
Secondary
Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90
Major vascular events included cardiovascular death, acute myocardial infarction (MI), or acute ischemic stroke. Participants may have had a vascular event in more than one category.
Time frame: At Day 10 + 5 days, at Day 35 + 6 days, and at Day 90 + 7 days
Population: Safety population: Participant had at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | Any event-Day 35 | 1.8 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | Any event-Day 10 | 1.0 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | Ischemic stroke-Day 35 | 0.5 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | Acute MI-Day 10 | 0.5 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | Acute MI-Day 35 | 0.6 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | Any event-Day 90 | 2.8 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | Death (cardiovascular)-Day 35 | 0.9 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | Ischemic stroke-Day 90 | 0.8 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | Acute MI-Day 90 | 0.9 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | Death (cardiovascular)-Day 10 | 0.4 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | Death (cardiovascular)-Day 90 | 1.4 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | Ischemic stroke-Day 10 | 0.3 Percentage of participants |
| Enoxaparin | Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | Death (cardiovascular)-Day 90 | 1.4 Percentage of participants |
| Enoxaparin | Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | Death (cardiovascular)-Day 35 | 0.8 Percentage of participants |
| Enoxaparin | Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | Ischemic stroke-Day 90 | 1.1 Percentage of participants |
| Enoxaparin | Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | Any event-Day 10 | 1.0 Percentage of participants |
| Enoxaparin | Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | Ischemic stroke-Day 10 | 0.3 Percentage of participants |
| Enoxaparin | Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | Acute MI-Day 10 | 0.4 Percentage of participants |
| Enoxaparin | Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | Death (cardiovascular)-Day 10 | 0.4 Percentage of participants |
| Enoxaparin | Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | Any event-Day 35 | 1.6 Percentage of participants |
| Enoxaparin | Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | Ischemic stroke-Day 35 | 0.5 Percentage of participants |
| Enoxaparin | Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | Any event-Day 90 | 2.8 Percentage of participants |
| Enoxaparin | Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | Acute MI-Day 90 | 0.7 Percentage of participants |
| Enoxaparin | Percentage of Participants With Major Vascular Events up to Days 10, 35, and 90 | Acute MI-Day 35 | 0.5 Percentage of participants |
Secondary
Percentage of Participants With Net Clinical Benefit (Any DVT, Non-fatal PE, VTE-related Death, Plus Major and Clinically Relevant Non-major Bleeding Events) up to Day 10 + 5 Days
Net clinical benefit is a composite of the primary efficacy endpoint (asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and VTE-related death) plus major and clinically relevant non-major bleeding events
Time frame: Up to Day 10 + 5 days
Population: Participants valid for safety analysis, with adequate assessment of VTE (to Day 10 within 48 hours of study drug), met inclusion criteria, and no major protocol deviations; expanded to include participants who had major bleeding or clinically relevant non-major bleeding events and met all criteria for PP except valid assessment of thromboembolism.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Net Clinical Benefit (Any DVT, Non-fatal PE, VTE-related Death, Plus Major and Clinically Relevant Non-major Bleeding Events) up to Day 10 + 5 Days | 4.5 Percentage of participants |
| Enoxaparin | Percentage of Participants With Net Clinical Benefit (Any DVT, Non-fatal PE, VTE-related Death, Plus Major and Clinically Relevant Non-major Bleeding Events) up to Day 10 + 5 Days | 3.9 Percentage of participants |
Secondary
Percentage of Participants With Net Clinical Benefit (Any DVT, Non-fatal PE, VTE-related Death, Plus Major and Clinically Relevant Non-major Bleeding Events) up to Day 35 + 6 Days
Net clinical benefit is a composite of the primary efficacy endpoint (asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and VTE-related death) plus major and clinically relevant non-major bleeding events.
Time frame: Up to Day 35 + 6 days
Population: modified Intent-to-Treat (mITT) Day 35 (participant was valid for the safety analysis and had an adequate assessment of VTE up to Day 35) expanded to include participants with major and clinically relevant bleeding events.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Net Clinical Benefit (Any DVT, Non-fatal PE, VTE-related Death, Plus Major and Clinically Relevant Non-major Bleeding Events) up to Day 35 + 6 Days | 9.4 Percentage of participants |
| Enoxaparin | Percentage of Participants With Net Clinical Benefit (Any DVT, Non-fatal PE, VTE-related Death, Plus Major and Clinically Relevant Non-major Bleeding Events) up to Day 35 + 6 Days | 7.8 Percentage of participants |
Secondary
Percentage of Participants With Symptomatic VTE, Including and Excluding VTE-related Death up to Days 10, 35, and 90
Symptomatic VTE (non-fatal PE and DVT in lower extremity), including and excluding VTE-related death (PE and PE cannot be excluded) up to Days 10, 35, and 90
Time frame: At Day 10 + 5 days, at Day 35 + 6 days, and at Day 90 + 7 days
Population: Safety population: Participant had at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Symptomatic VTE, Including and Excluding VTE-related Death up to Days 10, 35, and 90 | symptomatic VTE (incl. VTE-related death)-Day 35 | 1.0 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Symptomatic VTE, Including and Excluding VTE-related Death up to Days 10, 35, and 90 | symptomatic VTE (incl. VTE-related death)-Day 10 | 0.7 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Symptomatic VTE, Including and Excluding VTE-related Death up to Days 10, 35, and 90 | symptomatic VTE (non fatal)-Day 10 | 0.5 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Symptomatic VTE, Including and Excluding VTE-related Death up to Days 10, 35, and 90 | symptomatic VTE (non fatal)-Day 35 | 0.6 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Symptomatic VTE, Including and Excluding VTE-related Death up to Days 10, 35, and 90 | symptomatic VTE (incl. VTE-related death)-Day 90 | 1.7 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Symptomatic VTE, Including and Excluding VTE-related Death up to Days 10, 35, and 90 | symptomatic VTE (non fatal)-Day 90 | 0.7 Percentage of participants |
| Enoxaparin | Percentage of Participants With Symptomatic VTE, Including and Excluding VTE-related Death up to Days 10, 35, and 90 | symptomatic VTE (incl. VTE-related death)-Day 90 | 1.9 Percentage of participants |
| Enoxaparin | Percentage of Participants With Symptomatic VTE, Including and Excluding VTE-related Death up to Days 10, 35, and 90 | symptomatic VTE (incl. VTE-related death)-Day 35 | 1.4 Percentage of participants |
| Enoxaparin | Percentage of Participants With Symptomatic VTE, Including and Excluding VTE-related Death up to Days 10, 35, and 90 | symptomatic VTE (non fatal)-Day 35 | 0.7 Percentage of participants |
| Enoxaparin | Percentage of Participants With Symptomatic VTE, Including and Excluding VTE-related Death up to Days 10, 35, and 90 | symptomatic VTE (incl. VTE-related death)-Day 10 | 0.6 Percentage of participants |
| Enoxaparin | Percentage of Participants With Symptomatic VTE, Including and Excluding VTE-related Death up to Days 10, 35, and 90 | symptomatic VTE (non fatal)-Day 90 | 0.9 Percentage of participants |
| Enoxaparin | Percentage of Participants With Symptomatic VTE, Including and Excluding VTE-related Death up to Days 10, 35, and 90 | symptomatic VTE (non fatal)-Day 10 | 0.3 Percentage of participants |
Secondary
Percentage of Participants With the Composite of Treatment Emergent Major Bleeding Events and Non-major Clinically Relevant Bleeding Events up to 2 Days After Last Application of a Study Medication Syringe (Day 10 + 5 Days)
Major bleeding events were defined as events leading to \>=2 g/dL fall in hemoglobin or transfusion of \>=2 units of packed RBCs or whole blood or leading to death. Non-major bleeding events were defined as overt bleeding not meeting the criteria of major bleeding.
Time frame: Up to Day 10 + 5 days
Population: Safety population: Participant had at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With the Composite of Treatment Emergent Major Bleeding Events and Non-major Clinically Relevant Bleeding Events up to 2 Days After Last Application of a Study Medication Syringe (Day 10 + 5 Days) | 2.8 Percentage of participants |
| Enoxaparin | Percentage of Participants With the Composite of Treatment Emergent Major Bleeding Events and Non-major Clinically Relevant Bleeding Events up to 2 Days After Last Application of a Study Medication Syringe (Day 10 + 5 Days) | 1.2 Percentage of participants |
Comparison: There was no sample size estimation as this was not planed as confirmatory analysisp-value: <0.000195% CI: [1.628, 3.171]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With the Composite of Treatment Emergent Major Bleeding Events and Non-major Clinically Relevant Bleeding Events up to 2 Days After Last Intake of Any Study Medication (Day 35 + 6 Days)
Major bleeding events were defined as events leading to \>=2 g/dL fall in hemoglobin; or transfusion of \>= 2 units of packed RBCs (Red blood cells) or whole blood; or leading to death. Non-major bleeding events were defined as overt bleeding not meeting the criteria of major bleeding
Time frame: Up to Day 35 + 6 days
Population: Safety population: Participant had at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With the Composite of Treatment Emergent Major Bleeding Events and Non-major Clinically Relevant Bleeding Events up to 2 Days After Last Intake of Any Study Medication (Day 35 + 6 Days) | 4.1 Percentage of participants |
| Enoxaparin | Percentage of Participants With the Composite of Treatment Emergent Major Bleeding Events and Non-major Clinically Relevant Bleeding Events up to 2 Days After Last Intake of Any Study Medication (Day 35 + 6 Days) | 1.7 Percentage of participants |
Comparison: There was no sample size estimation as this was not planed as confirmatory analysisp-value: <0.000195% CI: [1.854, 3.251]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With VTE Combined With All-cause Mortality up to Day 10 + 5 Days
A composite endpoint of: asymptomatic proximal DVT in lower extremity detected by mandatory bilateral lower extremity venous ultrasonography; symptomatic DVT in lower extremity, proximal or distal; symptomatic, non-fatal PE; and death (VTE-related and not VTE-related).
Time frame: Up to Day 10 + 5 days
Population: modified Intent-to-Treat (mITT) Day 10 (participant was valid for the safety analysis and had an adequate assessment of VTE up to Day 10) expanded to include participants who had an assessment of all deaths, including not VTE-related
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With VTE Combined With All-cause Mortality up to Day 10 + 5 Days | 4.8 Percentage of participants |
| Enoxaparin | Percentage of Participants With VTE Combined With All-cause Mortality up to Day 10 + 5 Days | 4.5 Percentage of participants |