Pulmonary Embolism
Conditions
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 pulmonary embolism (PE) with or without symptomatic Deep-Vein Thrombosis (DVT) (Einstein-PE).
Detailed description
Within the US 'Johnson & Johnson Pharmaceutical Research & Development, L.L.C.' is sponsor.
Interventions
DRUGRivaroxaban (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.
DRUGEnoxaparin overlapping with and 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 hr before randomization if enoxaparin twice-daily was used. VKA should be started as soon as possible but not later than 48 hours after randomization.
Sponsors
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed acute symptomatic proximal PE with or without symptomatic DVT
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| Percentage of Participants With Recurrent 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 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. |
| 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. |
| 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. |
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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, 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. |
| 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. |
| 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. |
| Percentage of Participants With Symptomatic Recurrent VTE (i.e. the Composite of Recurrent DVT or Fatal or Non-fatal 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), and/or case summaries. |
| 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. |
Countries
Andorra, Australia, Austria, Belgium, Brazil, Canada, China, Czechia, Denmark, Estonia, Finland, France, Germany, Hong Kong, Hungary, India, Indonesia, Ireland, Israel, Italy, Latvia, Lithuania, Malaysia, Netherlands, New Zealand, Norway, Philippines, Poland, Puerto Rico, Singapore, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, United Kingdom, United States
Participant flow
Recruitment details
Participants with confirmed acute symptomatic pulmonary embolism (PE) with or without symptomatic deep vein thrombosis (DVT) were recruited at specialized study sites.
Pre-assignment details
Out of 4843 participants screened, 10 failed screening (6 due to protocol violations, 2 due to investigator decision and another 2 subjects due to technical problems \[interactive voice response system did not work properly\]). 4833 participants were randomized (2420 to rivaroxaban and 2413 to enoxaparin/VKA).
Participants by arm
| Arm | Count |
|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) Participants received 15 mg rivaroxaban (oral) twice daily (b.i.d.) for 3 weeks, followed by 20 mg once daily (o.d.) | 2,419 |
| Enoxaparin/VKA Participants received enoxaparin (subcutaneous) 1.0 mg/kg b.i.d. for minimal 5 days, plus vitamin K antagonist (VKA) at individually titrated doses to achieve a target international normalized ratio (INR) of 2.5 (range: 2.0 - 3.0) | 2,413 |
| Total | 4,832 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Observational Period | Death | 27 | 20 |
| Observational Period | Lack of Efficacy | 1 | 0 |
| Observational Period | Lost to Follow-up | 1 | 11 |
| Observational Period | Protocol driven decision point | 0 | 1 |
| Observational Period | Protocol Violation | 0 | 2 |
| Observational Period | Study terminated by sponsor | 3 | 1 |
| Observational Period | Technical problems | 0 | 1 |
| Observational Period | Withdrawal by Subject | 9 | 5 |
| Treatment Period | Adverse Event | 111 | 92 |
| Treatment Period | Clinical endpoint reached | 26 | 13 |
| Treatment Period | Death | 29 | 21 |
| Treatment Period | Did not take study treatment | 7 | 8 |
| Treatment Period | Lack of Efficacy | 1 | 4 |
| Treatment Period | Lost to Follow-up | 8 | 10 |
| Treatment Period | Participant convenience | 12 | 8 |
| Treatment Period | Physician Decision | 7 | 18 |
| Treatment Period | Protocol driven decision point | 1 | 3 |
| Treatment Period | Protocol Violation | 23 | 30 |
| Treatment Period | Site closed by investigator | 0 | 1 |
| Treatment Period | Study terminated by sponsor | 125 | 132 |
| Treatment Period | Technical problems | 3 | 1 |
| Treatment Period | Withdrawal by Subject | 66 | 118 |
Baseline characteristics
| Characteristic | Rivaroxaban (Xarelto, BAY59-7939) | Enoxaparin/VKA | Total |
|---|---|---|---|
| Age, Continuous | 57.9 Years STANDARD_DEVIATION 17.3 | 57.5 Years STANDARD_DEVIATION 17.2 | 57.7 Years STANDARD_DEVIATION 17.3 |
| Age, Customized 18 - < 40 years | 410 Participants | 432 Participants | 842 Participants |
| Age, Customized 40 - < 60 years | 794 Participants | 779 Participants | 1573 Participants |
| Age, Customized 60 - < 75 years | 740 Participants | 754 Participants | 1494 Participants |
| Age, Customized ≥ 75 years | 475 Participants | 448 Participants | 923 Participants |
| Sex: Female, Male Female | 1309 Participants | 1247 Participants | 2556 Participants |
| Sex: Female, Male Male | 1110 Participants | 1166 Participants | 2276 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1,053 / 2,412 | 1,065 / 2,405 |
| serious Total, serious adverse events | 504 / 2,412 | 495 / 2,405 |
Outcome results
Primary
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
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | 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 | 2.1 Percentage of participants |
| Enoxaparin/VKA | 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 | 1.8 Percentage of participants |
Comparison: 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.p-value: 0.002695% CI: [0.75, 1.68]Regression, Cox
Secondary
Percentage of Participants With All Deaths
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With All Deaths | Treatment-emergent (time window: 7 days) | 1.5 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With All Deaths | All post-randomization | 2.6 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With All Deaths | Treatment-emergent (time window: 2 days) | 1.2 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With All Deaths | All post-randomization | 2.1 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With All Deaths | Treatment-emergent (time window: 2 days) | 0.8 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With All Deaths | Treatment-emergent (time window: 7 days) | 1.1 Percentage of participants |
Secondary
Percentage of Participants With an Event for Net Clinical Benefit 1 Until the Intended End of Study Treatment
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With an Event for Net Clinical Benefit 1 Until the Intended End of Study Treatment | 3.4 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With an Event for Net Clinical Benefit 1 Until the Intended End of Study Treatment | 4.0 Percentage of participants |
p-value: 0.27595% CI: [0.63, 1.14]Regression, Cox
Secondary
Percentage of Participants With Clinically Relevant Bleeding, Treatment-emergent (Time Window: Until 2 Days After Last Dose)
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Clinically Relevant Bleeding, Treatment-emergent (Time Window: Until 2 Days After Last Dose) | 10.3 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With Clinically Relevant Bleeding, Treatment-emergent (Time Window: Until 2 Days After Last Dose) | 11.4 Percentage of participants |
p-value: 0.2395% CI: [0.76, 1.07]Regression, Cox
Secondary
Percentage of Participants With Other Vascular Events, On-treatment (Time Window: Until 1 Day After Last Dose)
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Other Vascular Events, On-treatment (Time Window: Until 1 Day After Last Dose) | 1.5 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With Other Vascular Events, On-treatment (Time Window: Until 1 Day After Last Dose) | 1.5 Percentage of participants |
Secondary
Percentage of Participants With Recurrent DVT Until the Intended End of Study Treatment
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Recurrent DVT Until the Intended End of Study Treatment | 0.7 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With Recurrent DVT Until the Intended End of Study Treatment | 0.8 Percentage of participants |
p-value: 0.8595% CI: [0.49, 1.79]Regression, Cox
Secondary
Percentage of Participants With Recurrent PE Until the Intended End of Study Treatment
All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on 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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Recurrent PE Until the Intended End of Study Treatment | 1.4 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With Recurrent PE Until the Intended End of Study Treatment | 1.2 Percentage of participants |
p-value: 0.5595% CI: [0.7, 1.93]Regression, Cox
Secondary
Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality Until the Intended End of Study Treatment
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality Until the Intended End of Study Treatment | 4.0 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality Until the Intended End of Study Treatment | 3.4 Percentage of participants |
Comparison: Stratified by intend treatment duration, adjusted for presence of active malignancy at baseline.p-value: 0.3395% CI: [0.86, 1.56]Regression, Cox
Other Pre-specified
Percentage of Participants With an Event for Net Clinical Benefit 1 During Observational 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.
Time frame: Up to 30 days after the last intake of study medication
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With an Event for Net Clinical Benefit 1 During Observational Period | 1.2 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With an Event for Net Clinical Benefit 1 During Observational Period | 1.2 Percentage of participants |
Post Hoc
Percentage of Participants With an Event for Net Clinical Benefit 2 During Observational Period
Net clinical benefit 2: composite of recurrent DVT or non-fatal or fatal PE, major 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 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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With an Event for Net Clinical Benefit 2 During Observational Period | 1.5 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With an Event for Net Clinical Benefit 2 During Observational Period | 1.4 Percentage of participants |
Post Hoc
Percentage of Participants With an Event for Net Clinical Benefit 2 Until the Intended End of Study Treatment
Net clinical benefit 2: composite of recurrent DVT or non-fatal or fatal PE, major 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 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: 3-, 6- or 12-month study treatment period
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With an Event for Net Clinical Benefit 2 Until the Intended End of Study Treatment | 4.5 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With an Event for Net Clinical Benefit 2 Until the Intended End of Study Treatment | 4.8 Percentage of participants |
Other Pre-specified
Percentage of Participants With Recurrent DVT During Observational 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.
Time frame: Up to 30 days after the last intake of study medication
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Recurrent DVT During Observational Period | 0.3 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With Recurrent DVT During Observational Period | 0.1 Percentage of participants |
Other Pre-specified
Percentage of Participants With Symptomatic Recurrent VTE (i.e. the Composite of Recurrent DVT or Fatal or Non-fatal PE) During Observational 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.
Time frame: Up to 30 days after the last intake of study medication
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Symptomatic Recurrent VTE (i.e. the Composite of Recurrent DVT or Fatal or Non-fatal PE) During Observational Period | 0.9 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With Symptomatic Recurrent VTE (i.e. the Composite of Recurrent DVT or Fatal or Non-fatal PE) During Observational Period | 0.7 Percentage of participants |
Other Pre-specified
Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality During Observational 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.
Time frame: Up to 30 days after the last intake of study medication
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality During Observational Period | 2.1 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality During Observational Period | 1.5 Percentage of participants |
Other Pre-specified
Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational 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.
Time frame: Up to 30 days after the last intake of study medication
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period | Death (PE cannot be excluded) | 0 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period | Death (bleeding) | 0.09 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period | Symptomatic recurrent PE only | 0.5 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period | Death (cardiovascular) | 0.3 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period | Symptomatic PE and DVT | 0.09 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period | Death (other) | 0.8 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period | Symptomatic recurrent DVT only | 0.2 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period | Major bleeding | 0.3 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period | Death (PE) | 0.09 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period | Major bleeding | 0.5 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period | Death (PE) | 0 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period | Death (PE cannot be excluded) | 0.05 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period | Symptomatic PE and DVT | 0 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period | Symptomatic recurrent PE only | 0.5 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period | Symptomatic recurrent DVT only | 0.1 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period | Death (bleeding) | 0.09 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period | Death (cardiovascular) | 0.05 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period | Death (other) | 0.7 Percentage of participants |
Other Pre-specified
Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment | Death (PE cannot be excluded) | 0.3 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment | Death (bleeding) | 0.2 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment | Symptomatic recurrent PE only | 1.0 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment | Death (cardiovascular) | 0.4 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment | Symptomatic PE and DVT | 0.0 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment | Death (other) | 1.3 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment | Symptomatic recurrent DVT only | 0.7 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment | Major bleeding | 1.4 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment | Death (PE) | 0.1 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment | Major bleeding | 2.4 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment | Death (PE) | 0.04 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment | Death (PE cannot be excluded) | 0.2 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment | Symptomatic PE and DVT | 0.1 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment | Symptomatic recurrent PE only | 0.8 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment | Symptomatic recurrent DVT only | 0.7 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment | Death (bleeding) | 0.2 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment | Death (cardiovascular) | 0.1 Percentage of participants |
| Enoxaparin/VKA | Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment | Death (other) | 1.5 Percentage of participants |