Venous Thromboembolism
Conditions
Keywords
Prevention of venous thromboembolism
Brief summary
The purpose of this study is to assess if 10 mg BAY59-7939, taken once daily as a tablet, is safe and prevents blood clot which may form after a knee replacement operation.
Interventions
DRUGRivaroxaban (Xarelto, BAY59-7939)
Rivaroxaban (Xarelto, BAY59-7939) 10 mg tablet administered once daily (od) in the evening.
DRUGEnoxaparin
Syringes of enoxaparin active substance 30 mg twice a day administered once in the morning and once in the evening.
DRUGPlacebo: tablet of Rivaroxaban
Placebo tablet of rivaroxaban administered once daily in the evening.
DRUGPlacebo: syringes of Enoxaparin
Placebo syringes of enoxaparin twice a day (bid) administered once in the morning and once in the evening.
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female patients aged 18 years or above * Patients scheduled for elective total knee replacement
Exclusion criteria
* Active bleeding or high risk of bleeding contraindicating treatment with Low Molecular Weight Heparin (LMWH) * Contraindication listed in the labeling or conditions precluding subject treatment with enoxaparin or requiring dose adjustment (e.g. severe renal impairment, please refer to the local label of enoxaparin in your country) * Conditions prohibiting bilateral venography (e.g. amputation of 1 leg, allergy to contrast media)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite Endpoint of Total Venous Thrombo Embolism (VTE) i.e.: Any Deep Vein Thromboembolism (DVT) (Proximal and/or Distal), Non Fatal Pulmonary Embolism (PE), Death of All Causes Per Protocol Population | Up to 16 days after surgery | Blinded, adjudicated assessment of bilateral venography, clinical signs of deep vein thrombosis (DVT) and pulmonary embolism (PE), ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography |
| Composite Endpoint of Total VTE i.e.: Any DVT (Proximal and/or Distal), Non Fatal PE, Death of All Causes Per Modified Intent to Treat Population. | Up to 16 days after surgery | Blinded, adjudicated assessment of bilateral venography, clinical signs of deep vein thrombosis (DVT) and pulmonary embolism (PE), ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Symptomatic VTE (DVT, PE) Per Protocol Population. | Up to 16 days after surgery | Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography |
| Incidence of Symptomatic VTE (DVT, PE) Per Modified Intent to Treat Population. | Up to 16 days after surgery | Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography |
| Incidence of DVT (Proximal, Distal) Per Protocol Population. | Up to 16 days after surgery | Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography |
| Incidence of DVT (Proximal, Distal) Per Modified Intent to Treat Population. | Up to 16 days after surgery | Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography |
| Incidence of Symptomatic VTE During Follow-up Per Protocol Population. | Up to 47 days after surgery | Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography |
| Incidence of Symptomatic VTE During Follow-up Per Modified Intent to Treat Population. | Up to 47 days after surgery | Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography |
| Incidence of the Composite Endpoint Comprising Proximal DVT, Non-fatal PE and VTE- Related Death (Major VTE) Per Protocol Population of Major VTE | Up to 16 days after surgery | Blinded, adjudicated assessment of bilateral venography, clinical signs of deep vein thrombosis (DVT) and pulmonary embolism (PE), ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography |
| Incidence of the Composite Endpoint That Results From the Primary Endpoint by Substituting VTE Related Death for All Death Per Protocol Population. | Up to 16 days after surgery | Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography |
| Incidence of the Composite Endpoint That Results From the Primary Endpoint by Substituting VTE Related Death for All Death Per Modified Intent to Treat Population. | Up to 16 days after surgery | Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography |
| Incidence of the Composite Endpoint That Results From Major VTE by Substituting All Cause Mortality for VTE-related Death Per Protocol of Major VTE Population. | Up to 16 days after surgery | Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography |
| Incidence of the Composite Endpoint That Results From Major VTE by Substituting All Cause Mortality for VTE-related Death Per Modified Intent to Treat of Major VTE Population. | Up to 16 days after surgery | Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography |
| Treatment-emergent Major Bleedings Per Safety Population. | from start of double-blind study medication to last dose of double-blind study medication plus two days. The average duration of double-blind treatment was 12 days in each treatment group (safety population). | Blinded, adjudicated assessments of all available information (eg, anesthesia and surgery reports, laboratory results, number of transfusions, autopsy report) |
| The Composite Endpoint Comprising Major VTE and Treatment-emergent Major Bleeding Per Subjects Valid for Analysis of Net Clinical Benefit | Up to 47 days after surgery | Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography, anesthesia and surgery reports, number of transfusions |
| Incidence of the Composite Endpoint Comprising Proximal DVT, Non-fatal PE and VTE- Related Death (Major VTE) Per Modified Intent to Treat Population of Major VTE. | Up to 16 days after surgery | Blinded, adjudicated assessment of bilateral venography, clinical signs of deep vein thrombosis (DVT) and pulmonary embolism (PE), ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography |
Countries
Bulgaria, Canada, Denmark, India, Israel, Lithuania, Mexico, Norway, Pakistan, Poland, Sri Lanka, Sweden, United States
Participant flow
Recruitment details
The recruitment period was from 16 Jun 2006 to 31 Jan 2008.
Pre-assignment details
3418 subjects were screened; 270 subjects were screening failures and were not randomized; 3148 subjects were randomized; 114 subjects did not receive medication; 3034 subjects received medication and were included in the safety population
Participants by arm
| Arm | Count |
|---|---|
| Rivaroxaban 10 mg Once Daily (OD) (Xarelto, BAY59-7939) Rivaroxaban (Xarelto, BAY59-7939) 10 mg tablet administered once daily (od) in the evening plus placebo syringes of enoxaparin twice a day (bid) administered once in the morning and once in the evening. | 1,526 |
| Enoxaparin 30 mg Twice a Day (Bid) Placebo tablet of rivaroxaban administered once daily in the evening plus syringes of enoxaparin active substance 30 mg twice a day administered once in the morning and once in the evening. | 1,508 |
| Total | 3,034 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Follow-up (30 (+ 5) Days) | Adverse Event | 2 | 3 |
| Follow-up (30 (+ 5) Days) | Death | 1 | 1 |
| Follow-up (30 (+ 5) Days) | Lost to Follow-up | 27 | 28 |
| Follow-up (30 (+ 5) Days) | Withdrawal by Subject | 8 | 7 |
| Treatment (12 +/- 2 Days) | Adverse Event | 62 | 56 |
| Treatment (12 +/- 2 Days) | Clinical Endpoint Reached | 10 | 18 |
| Treatment (12 +/- 2 Days) | Death | 1 | 3 |
| Treatment (12 +/- 2 Days) | Lost to Follow-up | 3 | 1 |
| Treatment (12 +/- 2 Days) | Noncompliance to Study Drug | 9 | 0 |
| Treatment (12 +/- 2 Days) | Physician Decision | 2 | 5 |
| Treatment (12 +/- 2 Days) | Protocol Violation | 22 | 21 |
| Treatment (12 +/- 2 Days) | Technical Problems | 1 | 0 |
| Treatment (12 +/- 2 Days) | Withdrawal by Subject | 49 | 47 |
Baseline characteristics
| Characteristic | Total | Rivaroxaban 10 mg Once Daily (OD) (Xarelto, BAY59-7939) | Enoxaparin 30 mg Twice a Day (Bid) |
|---|---|---|---|
| Age, Continuous | 64.5 years STANDARD_DEVIATION 9.7 | 64.4 years STANDARD_DEVIATION 9.7 | 64.7 years STANDARD_DEVIATION 9.7 |
| Race/Ethnicity, Customized American Indian | 5 participants | 1 participants | 4 participants |
| Race/Ethnicity, Customized Asian | 578 participants | 289 participants | 289 participants |
| Race/Ethnicity, Customized Black | 153 participants | 88 participants | 65 participants |
| Race/Ethnicity, Customized Hispanic | 253 participants | 137 participants | 116 participants |
| Race/Ethnicity, Customized Uncodable | 4 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized White | 2040 participants | 1008 participants | 1032 participants |
| Sex: Female, Male Female | 1974 Participants | 1007 Participants | 967 Participants |
| Sex: Female, Male Male | 1060 Participants | 519 Participants | 541 Participants |
| Weight > 110 kg | 347 participants | 185 participants | 162 participants |
| Weight > 50 - 70 kg | 725 participants | 367 participants | 358 participants |
| Weight =< 50 kg | 50 participants | 22 participants | 28 participants |
| Weight > 70 - 90 kg | 1245 participants | 629 participants | 616 participants |
| Weight > 90 - 110 kg | 665 participants | 322 participants | 343 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1,167 / 1,526 | 1,152 / 1,508 |
| serious Total, serious adverse events | 106 / 1,526 | 131 / 1,508 |
Outcome results
Primary
Composite Endpoint of Total Venous Thrombo Embolism (VTE) i.e.: Any Deep Vein Thromboembolism (DVT) (Proximal and/or Distal), Non Fatal Pulmonary Embolism (PE), Death of All Causes Per Protocol Population
Blinded, adjudicated assessment of bilateral venography, clinical signs of deep vein thrombosis (DVT) and pulmonary embolism (PE), ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography
Time frame: Up to 16 days after surgery
Population: The primary efficacy analysis was based on the per protocol (PP) population and included subjects who were valid for the modified intent to treat (MITT) population, had an adequate assessment of thromboembolism that, in case of a positive finding, was done not later than 36 hours after stop of study drug, and had no major protocol deviations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban 10 mg Once Daily (OD) (Xarelto, BAY59-7939) | Composite Endpoint of Total Venous Thrombo Embolism (VTE) i.e.: Any Deep Vein Thromboembolism (DVT) (Proximal and/or Distal), Non Fatal Pulmonary Embolism (PE), Death of All Causes Per Protocol Population | 6.71 Percentage of participants |
| Enoxaparin 30 mg Twice a Day (Bid) | Composite Endpoint of Total Venous Thrombo Embolism (VTE) i.e.: Any Deep Vein Thromboembolism (DVT) (Proximal and/or Distal), Non Fatal Pulmonary Embolism (PE), Death of All Causes Per Protocol Population | 9.34 Percentage of participants |
Comparison: Null hypothesis: rivaroxaban is inferior to the comparator, ie, the incidence of the primary efficacy endpoint in the rivaroxaban group is larger by more than 4% (absolute) compared to the comparator group.p-value: <0.00195% CI: [-5.25, -0.17]Mantel Haenszel
Comparison: Null hypothesis: The incidence of the primary efficacy endpoint is equal in the rivaroxaban group and the comparator group. P-values were calculated based on the Mantel-Haenszel weighted estimator (two-sided).p-value: 0.03695% CI: [-5.25, -0.17]Mantel Haenszel
Primary
Composite Endpoint of Total VTE i.e.: Any DVT (Proximal and/or Distal), Non Fatal PE, Death of All Causes Per Modified Intent to Treat Population.
Blinded, adjudicated assessment of bilateral venography, clinical signs of deep vein thrombosis (DVT) and pulmonary embolism (PE), ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography
Time frame: Up to 16 days after surgery
Population: A subject was considered valid for the MITT analysis if the subject was valid for the safety analysis, had undergone the appropriate surgery, and had an adequate assessment of thromboembolism
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban 10 mg Once Daily (OD) (Xarelto, BAY59-7939) | Composite Endpoint of Total VTE i.e.: Any DVT (Proximal and/or Distal), Non Fatal PE, Death of All Causes Per Modified Intent to Treat Population. | 6.94 Percentage of participants |
| Enoxaparin 30 mg Twice a Day (Bid) | Composite Endpoint of Total VTE i.e.: Any DVT (Proximal and/or Distal), Non Fatal PE, Death of All Causes Per Modified Intent to Treat Population. | 10.11 Percentage of participants |
Comparison: Null hypothesis: The incidence of the primary efficacy endpoint is equal in the rivaroxaban group and the comparator group. P-values were calculated based on the Mantel-Haenszel weighted estimator (two-sided).p-value: 0.01295% CI: [-5.67, -0.71]Mantel Haenszel
Secondary
Incidence of DVT (Proximal, Distal) Per Modified Intent to Treat Population.
Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography
Time frame: Up to 16 days after surgery
Population: A subject was considered valid for the MITT analysis if the subject was valid for the safety analysis, had undergone the appropriate surgery, and had an adequate assessment of thromboembolism
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban 10 mg Once Daily (OD) (Xarelto, BAY59-7939) | Incidence of DVT (Proximal, Distal) Per Modified Intent to Treat Population. | 6.32 percentage of participants |
| Enoxaparin 30 mg Twice a Day (Bid) | Incidence of DVT (Proximal, Distal) Per Modified Intent to Treat Population. | 8.97 percentage of participants |
95% CI: [-5.02, -0.32]
Secondary
Incidence of DVT (Proximal, Distal) Per Protocol Population.
Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography
Time frame: Up to 16 days after surgery
Population: The PP population included subjects who were valid for the modified intent to treat (MITT) population, had an adequate assessment of thromboembolism that, in case of a positive finding, was done not later than 36 hours after stop of study drug, and had no major protocol deviations
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban 10 mg Once Daily (OD) (Xarelto, BAY59-7939) | Incidence of DVT (Proximal, Distal) Per Protocol Population. | 6.37 percentage of participants |
| Enoxaparin 30 mg Twice a Day (Bid) | Incidence of DVT (Proximal, Distal) Per Protocol Population. | 8.66 percentage of participants |
95% CI: [-4.84, 0.07]
Secondary
Incidence of Symptomatic VTE During Follow-up Per Modified Intent to Treat Population.
Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography
Time frame: Up to 47 days after surgery
Population: A subject was considered valid for the MITT analysis if the subject was valid for the safety analysis, had undergone the appropriate surgery, and had an adequate assessment of thromboembolism
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban 10 mg Once Daily (OD) (Xarelto, BAY59-7939) | Incidence of Symptomatic VTE During Follow-up Per Modified Intent to Treat Population. | 0.31 percentage of participants |
| Enoxaparin 30 mg Twice a Day (Bid) | Incidence of Symptomatic VTE During Follow-up Per Modified Intent to Treat Population. | 0.21 percentage of participants |
95% CI: [-0.35, 0.56]
Secondary
Incidence of Symptomatic VTE During Follow-up Per Protocol Population.
Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography
Time frame: Up to 47 days after surgery
Population: The PP population included subjects who were valid for the modified intent to treat (MITT) population, had an adequate assessment of thromboembolism that, in case of a positive finding, was done not later than 36 hours after stop of study drug, and had no major protocol deviations
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban 10 mg Once Daily (OD) (Xarelto, BAY59-7939) | Incidence of Symptomatic VTE During Follow-up Per Protocol Population. | 0.35 percentage of participants |
| Enoxaparin 30 mg Twice a Day (Bid) | Incidence of Symptomatic VTE During Follow-up Per Protocol Population. | 0.11 percentage of participants |
95% CI: [-0.22, 0.71]
Secondary
Incidence of Symptomatic VTE (DVT, PE) Per Modified Intent to Treat Population.
Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography
Time frame: Up to 16 days after surgery
Population: A subject was considered valid for the MITT analysis if the subject was valid for the safety analysis, had undergone the appropriate surgery, and had an adequate assessment of thromboembolism
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban 10 mg Once Daily (OD) (Xarelto, BAY59-7939) | Incidence of Symptomatic VTE (DVT, PE) Per Modified Intent to Treat Population. | 1.14 percentage of participants |
| Enoxaparin 30 mg Twice a Day (Bid) | Incidence of Symptomatic VTE (DVT, PE) Per Modified Intent to Treat Population. | 1.88 percentage of participants |
95% CI: [-1.81, 0.36]
Secondary
Incidence of Symptomatic VTE (DVT, PE) Per Protocol Population.
Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography
Time frame: Up to 16 days after surgery
Population: The PP population included subjects who were valid for the modified intent to treat (MITT) population, had an adequate assessment of thromboembolism that, in case of a positive finding, was done not later than 36 hours after stop of study drug, and had no major protocol deviations
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban 10 mg Once Daily (OD) (Xarelto, BAY59-7939) | Incidence of Symptomatic VTE (DVT, PE) Per Protocol Population. | 1.04 percentage of participants |
| Enoxaparin 30 mg Twice a Day (Bid) | Incidence of Symptomatic VTE (DVT, PE) Per Protocol Population. | 1.48 percentage of participants |
95% CI: [-1.59, 0.66]
Secondary
Incidence of the Composite Endpoint Comprising Proximal DVT, Non-fatal PE and VTE- Related Death (Major VTE) Per Modified Intent to Treat Population of Major VTE.
Blinded, adjudicated assessment of bilateral venography, clinical signs of deep vein thrombosis (DVT) and pulmonary embolism (PE), ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography
Time frame: Up to 16 days after surgery
Population: A subject was considered valid for the MITT analysis if the subject was valid for the safety analysis, had undergone the appropriate surgery, and had an adequate assessment of thromboembolism
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban 10 mg Once Daily (OD) (Xarelto, BAY59-7939) | Incidence of the Composite Endpoint Comprising Proximal DVT, Non-fatal PE and VTE- Related Death (Major VTE) Per Modified Intent to Treat Population of Major VTE. | 1.16 percentage of participants |
| Enoxaparin 30 mg Twice a Day (Bid) | Incidence of the Composite Endpoint Comprising Proximal DVT, Non-fatal PE and VTE- Related Death (Major VTE) Per Modified Intent to Treat Population of Major VTE. | 1.98 percentage of participants |
Comparison: Null hypothesis: The incidence of the major VTE is equal in the rivaroxaban group and the comparator group. P-values were calculated based on the Mantel-Haenszel weighted estimator (two-sided)p-value: 0.12495% CI: [-1.82, 0.22]Mantel Haenszel
Comparison: Null hypothesis: rivaroxaban is inferior to the comparator, ie, the incidence of the major VTE in the rivaroxaban group is larger by more than 1.5% (absolute) compared to the comparator group.p-value: <0.00195% CI: [-1.82, 0.22]Mantel Haenszel
Secondary
Incidence of the Composite Endpoint Comprising Proximal DVT, Non-fatal PE and VTE- Related Death (Major VTE) Per Protocol Population of Major VTE
Blinded, adjudicated assessment of bilateral venography, clinical signs of deep vein thrombosis (DVT) and pulmonary embolism (PE), ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography
Time frame: Up to 16 days after surgery
Population: The PP population included subjects who were valid for the modified intent to treat (MITT) population, had an adequate assessment of thromboembolism that, in case of a positive finding, was done not later than 36 hours after stop of study drug, and had no major protocol deviations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban 10 mg Once Daily (OD) (Xarelto, BAY59-7939) | Incidence of the Composite Endpoint Comprising Proximal DVT, Non-fatal PE and VTE- Related Death (Major VTE) Per Protocol Population of Major VTE | 1.09 percentage of participants |
| Enoxaparin 30 mg Twice a Day (Bid) | Incidence of the Composite Endpoint Comprising Proximal DVT, Non-fatal PE and VTE- Related Death (Major VTE) Per Protocol Population of Major VTE | 1.47 percentage of participants |
Comparison: Null hypothesis: The incidence of the major VTE is equal in the rivaroxaban group and the comparator group. P-values were calculated based on the Mantel-Haenszel weighted estimator (two-sided)p-value: 0.45695% CI: [-1.34, 0.6]Mantel Haenszel
Comparison: Null hypothesis: rivaroxaban is inferior to the comparator, ie, the incidence of the major VTE in the rivaroxaban group is larger by more than 1.5% (absolute) compared to the comparator group.p-value: <0.00195% CI: [-1.34, 0.6]Mantel Haenszel
Secondary
Incidence of the Composite Endpoint That Results From Major VTE by Substituting All Cause Mortality for VTE-related Death Per Modified Intent to Treat of Major VTE Population.
Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography
Time frame: Up to 16 days after surgery
Population: A subject was considered valid for the MITT analysis if the subject was valid for the safety analysis, had undergone the appropriate surgery, and had an adequate assessment of thromboembolism
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban 10 mg Once Daily (OD) (Xarelto, BAY59-7939) | Incidence of the Composite Endpoint That Results From Major VTE by Substituting All Cause Mortality for VTE-related Death Per Modified Intent to Treat of Major VTE Population. | 1.25 percentage of participants |
| Enoxaparin 30 mg Twice a Day (Bid) | Incidence of the Composite Endpoint That Results From Major VTE by Substituting All Cause Mortality for VTE-related Death Per Modified Intent to Treat of Major VTE Population. | 2.25 percentage of participants |
Comparison: Null hypothesis: The incidence rate is equal in the rivaroxaban group and the comparator group. P-values were calculated based on the Mantel-Haenszel weighted estimator (two-sided)p-value: 0.07495% CI: [-2.06, 0.1]Mantel Haenszel
Comparison: Null hypothesis: rivaroxaban is inferior to the comparator, ie, the incidence rate in the rivaroxaban group is larger by more than 1.5% (absolute) compared to the comparator group.p-value: <0.00195% CI: [-2.06, 0.1]Mantel Haenszel
Secondary
Incidence of the Composite Endpoint That Results From Major VTE by Substituting All Cause Mortality for VTE-related Death Per Protocol of Major VTE Population.
Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography
Time frame: Up to 16 days after surgery
Population: The PP population included subjects who were valid for the modified intent to treat (MITT) population, had an adequate assessment of thromboembolism that, in case of a positive finding, was done not later than 36 hours after stop of study drug, and had no major protocol deviations
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban 10 mg Once Daily (OD) (Xarelto, BAY59-7939) | Incidence of the Composite Endpoint That Results From Major VTE by Substituting All Cause Mortality for VTE-related Death Per Protocol of Major VTE Population. | 1.09 percentage of participants |
| Enoxaparin 30 mg Twice a Day (Bid) | Incidence of the Composite Endpoint That Results From Major VTE by Substituting All Cause Mortality for VTE-related Death Per Protocol of Major VTE Population. | 1.67 percentage of participants |
Comparison: Null hypothesis: The incidence rate is equal in the rivaroxaban group and the comparator group. P-values were calculated based on the Mantel-Haenszel weighted estimator (two-sided)p-value: 0.2795% CI: [-1.57, 0.44]Mantel Haenszel
Comparison: Null hypothesis: rivaroxaban is inferior to the comparator, ie, the incidence rate in the rivaroxaban group is larger by more than 1.5% (absolute) compared to the comparator group.p-value: <0.00195% CI: [-1.57, 0.44]Mantel Haenszel
Secondary
Incidence of the Composite Endpoint That Results From the Primary Endpoint by Substituting VTE Related Death for All Death Per Modified Intent to Treat Population.
Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography
Time frame: Up to 16 days after surgery
Population: A subject was considered valid for the MITT analysis if the subject was valid for the safety analysis, had undergone the appropriate surgery, and had an adequate assessment of thromboembolism
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban 10 mg Once Daily (OD) (Xarelto, BAY59-7939) | Incidence of the Composite Endpoint That Results From the Primary Endpoint by Substituting VTE Related Death for All Death Per Modified Intent to Treat Population. | 6.84 percentage of participants |
| Enoxaparin 30 mg Twice a Day (Bid) | Incidence of the Composite Endpoint That Results From the Primary Endpoint by Substituting VTE Related Death for All Death Per Modified Intent to Treat Population. | 9.80 percentage of participants |
Comparison: Null hypothesis: The incidence rate is equal in the rivaroxaban group and the comparator group. P-values were calculated based on the Mantel-Haenszel weighted estimator (two-sided)p-value: 0.01795% CI: [-5.42, -0.53]Mantel Haenszel
Comparison: Null hypothesis: rivaroxaban is inferior to the comparator, ie, the incidence rate in the rivaroxaban group is larger by more than 4% (absolute) compared to the comparator group.p-value: <0.00195% CI: [-5.42, -0.53]Mantel Haenszel
Secondary
Incidence of the Composite Endpoint That Results From the Primary Endpoint by Substituting VTE Related Death for All Death Per Protocol Population.
Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography
Time frame: Up to 16 days after surgery
Population: The PP population included subjects who were valid for the modified intent to treat (MITT) population, had an adequate assessment of thromboembolism that, in case of a positive finding, was done not later than 36 hours after stop of study drug, and had no major protocol deviations
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban 10 mg Once Daily (OD) (Xarelto, BAY59-7939) | Incidence of the Composite Endpoint That Results From the Primary Endpoint by Substituting VTE Related Death for All Death Per Protocol Population. | 6.71 percentage of participants |
| Enoxaparin 30 mg Twice a Day (Bid) | Incidence of the Composite Endpoint That Results From the Primary Endpoint by Substituting VTE Related Death for All Death Per Protocol Population. | 9.11 percentage of participants |
Comparison: Null hypothesis: The incidence rate is equal in the rivaroxaban group and the comparator group. P-values were calculated based on the Mantel-Haenszel weighted estimator (two-sided)p-value: 0.05495% CI: [-4.99, 0.04]Mantel Haenszel
Comparison: Null hypothesis: rivaroxaban is inferior to the comparator, ie, the incidence rate in the rivaroxaban group is larger by more than 4% (absolute) compared to the comparator group.p-value: <0.00195% CI: [-4.49, 0.04]Mantel Haenszel
Secondary
The Composite Endpoint Comprising Major VTE and Treatment-emergent Major Bleeding Per Subjects Valid for Analysis of Net Clinical Benefit
Blinded, adjudicated assessment of bilateral venography, clinical signs of DVT and PE, ultrasound, clinical chemistry and coagulation factors, autopsy report, electrocardiogram (ECG), pulmonary angiography, perfusion/ventilation lung scintigraphy, chest radiography, computed tomography, anesthesia and surgery reports, number of transfusions
Time frame: Up to 47 days after surgery
Population: The net clinical benefit population comprised all subjects either valid for MITT analysis of major VTE or who showed treatment-emergent major bleeding.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban 10 mg Once Daily (OD) (Xarelto, BAY59-7939) | The Composite Endpoint Comprising Major VTE and Treatment-emergent Major Bleeding Per Subjects Valid for Analysis of Net Clinical Benefit | 2.04 percentage of participants |
| Enoxaparin 30 mg Twice a Day (Bid) | The Composite Endpoint Comprising Major VTE and Treatment-emergent Major Bleeding Per Subjects Valid for Analysis of Net Clinical Benefit | 2.33 percentage of participants |
95% CI: [-1.56, 0.94]
Secondary
Treatment-emergent Major Bleedings Per Safety Population.
Blinded, adjudicated assessments of all available information (eg, anesthesia and surgery reports, laboratory results, number of transfusions, autopsy report)
Time frame: from start of double-blind study medication to last dose of double-blind study medication plus two days. The average duration of double-blind treatment was 12 days in each treatment group (safety population).
Population: The safety population comprised those subjects who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban 10 mg Once Daily (OD) (Xarelto, BAY59-7939) | Treatment-emergent Major Bleedings Per Safety Population. | 0.66 percentage of participants |
| Enoxaparin 30 mg Twice a Day (Bid) | Treatment-emergent Major Bleedings Per Safety Population. | 0.27 percentage of participants |
Comparison: Null hypothesis: The incidence rate is equal in the rivaroxaban group and the comparator group. P-values were calculated based on the Mantel-Haenszel weighted estimator (two-sided)p-value: 0.1195% CI: [-0.09, 0.88]Mantel Haenszel