Venous Thromboembolism
Conditions
Brief summary
This is a multicenter, randomized, double-blind, placebo-controlled, event-driven, superiority study for efficacy. Patients with confirmed symptomatic DVT (deep vein thrombosis) or PE (pulmonary embolism) who completed 6 or 12 months of treatment with rivaroxaban or VKA (vitamin K antagonist) are eligible for this trial (Einstein-Extension study).
Detailed description
Within the US 'Johnson & Johnson Pharmaceutical Research & Development, L.L.C.' is sponsor. The treatment period was followed by an observational period of 30 days starting the day after the last intake of study medication, regardless of the actual duration of study drug administration. Participants who did not complete the treatment period also entered the observational period. It was also possible that participants did not enter the observational period, e.g. due to withdrawal of consent or termination of study participation.
Interventions
DRUGRivaroxaban (Xarelto, BAY59-7939)
Patients randomized to rivaroxaban will receive rivaroxaban 20 mg once-daily.
DRUGPlacebo
Patients allocated to placebo will receive a matching placebo tablet once daily.
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
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with confirmed symptomatic PE or DVT who have been treated for 6 or 12 months with VKA or rivaroxaban
Exclusion criteria
* Legal lower age limitations (country specific) * Indication for VKA other than DVT and/or PE * Patients in whom anticoagulant treatment for their index PE or DVT should be continued * Childbearing potential without proper contraceptive measures, pregnancy or breast feeding. Proper contraceptive measures are defined as a method of contraception with a failure rate \< 1 % during the course of the study (including the observational period). These methods of contraception according to the note for guidance on non-clinical safety studies for the conduct of human trials for pharmaceuticals (CPMP \[Committee for Proprietary Medicinal Products\]/ICH \[International Conference on Harmonization\]/286/95, modification) include consistent and correct use of hormone containing implants and injectables, combined oral contraceptives, hormone containing intrauterine devices, surgical sterilization, sexual abstinence and vasectomy
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 | 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. For definition of DVT/PE, kindly refer to the link in the Protocol section. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality Until the Intended End of Study Treatment | 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), or lung scintigraphy (for PE), and/or case summaries. |
| Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE, All Cause Mortality, Strokes and Myocardial Infarctions Until the Intended End of Study Treatment | 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), results/films/images of confirmatory testing, and/or case summaries. |
| Percentage of Participants With Net Clinical Benefit as Composite of Recurrent DVT or Non-fatal or Fatal PE and Major Bleeding Events Until the Intended End of Study Treatment | 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. |
| Percentage of Participants With Recurrent VTE (PE or DVT) Until the Intended End of Study Treatment | 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), results/films/images of confirmatory testing, and/or case summaries. |
| Percentage of Participants With Recurrent DVT Until the Intended End of Study Treatment | 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 Major Bleeding | 6- or 12-month study treatment period | All events were adjudicated and confirmed by a central independent adjudication committee (CIAC) blinded to treatment. Major bleeding event was overt bleeding associated with a 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. Treatment-emergent \[after intake of first tablet of study medication as randomized but not more than 2 days after stop of study medication (referred to as time window: 2 days)\] events and all events post randomization were reported. |
| Percentage of Participants With Clinically Relevant Bleeding | 6- or 12-month study treatment period | All events adjudicated/confirmed by CIAC blinded to treatment. Clinically relevant bleeding included major bleeding (definition: see outcome 7) 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 daily life activities. Treatment-emergent events (after intake of 1st study medication tablet as randomized up to 2 days after stop of study medication \['time window: 2 days'\]) and all events post randomization were reported |
| Percentage of Participants With All Death | 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. Treatment-emergent events and all events post randomization were reported. Treatment-emergent: after intake of first tablet of study medication as randomized but not more than 2 days after stop of study medication (referred to as time window: 2 days) |
| Percentage of Participants With Other Vascular Events | 6- or 12-month study treatment period | All pre-defined vascular events (acute coronary syndromes, ischemic stroke, transient ischemic attack, non-central nervous system systemic embolism and vascular death) were adjudicated/confirmed by a central independent adjudication committee blinded to treatment, based on results/films/images of confirmatory testing, and/or case summaries. On treatment events and all events post randomization were reported. On treatment: after intake of first tablet of study medication as randomized but not more than 1 day after stop of study medication (referred to as time window: 1 day) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Death (PE) Until the Intended End of Study Treatment | 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 Death (PE Cannot be Excluded) Until the Intended End of Study Treatment | 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 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 Symptomatic Recurrent PE Until the Intended End of Study Treatment | 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 spiral computed tomography (CT) scanning, pulmonary angiography, ventilation/perfusion lung scan, lung scintigraphy, results/films/images of confirmatory testing, and/or case summaries. |
| Percentage of Participants With Symptomatic Recurrent Venous Thromboembolism [VTE] (i.e. the Composite of Recurrent Deep Vein Thrombosis [DVT] or Fatal or Non-fatal Pulmonary Embolism [PE]) During Observational Period | 30 days observational period after last intake of study medication | All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound (for DVT), venography (for DVT), spiral computed tomography (CT) scanning (for PE), pulmonary angiography (for PE), ventilation/perfusion lung scan (for PE), lung scintigraphy (for PE), autopsy (for fatal PE) or unexplained death for which DVT/PE could not be ruled out (for fatal PE), results/films/images of confirmatory testing, and/or case summaries. |
| Percentage of Participants With Symptomatic Recurrent PE During Observational Period | 30 days observational period after 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 spiral computed tomography (CT) scanning, pulmonary angiography, ventilation/perfusion lung scan, lung scintigraphy, 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 During Observational Period | 30 days observational period after 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 the Composite Variable Comprising Recurrent DVT, Non-fatal PE, All Cause Mortality, Strokes and Myocardial Infarctions During Observational Period | 30 days observational period after last intake of study medication | All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound (for DVT), venography (for DVT), spiral computed tomography (CT) scanning (for PE), pulmonary angiography (for PE), ventilation/perfusion lung scan (for PE), lung scintigraphy (for PE), autopsy (for fatal PE) or unexplained death for which DVT/PE could not be ruled out (for fatal PE), results/films/images of confirmatory testing, and/or case summaries. |
| Percentage of Participants With Net Clinical Benefit as Composite of Recurrent DVT or Non-fatal or Fatal PE and Major Bleeding Events During Observational Period | 30 days observational period after last intake of study medication | Events were adjudicated/confirmed by a central independent adjudication committee blinded to treatment, based on either compression ultrasound, venography, spiral CT 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 or more units, occurring in a critical site or contributing to death. |
| Percentage of Participants With Recurrent VTE (PE or DVT) During Observational Period | 30 days observational period after 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), results/films/images of confirmatory testing, and/or case summaries. |
| Percentage of Participants With Recurrent DVT During Observational Period | 30 days observational period after 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 or venography, results/films/images of confirmatory testing, and/or case summaries. |
Countries
Australia, Austria, Belgium, Brazil, Canada, China, Czechia, Denmark, Finland, France, Germany, Hong Kong, Hungary, India, Indonesia, Israel, Italy, Malaysia, Netherlands, New Zealand, Norway, Philippines, Poland, Singapore, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, United Kingdom, United States
Participant flow
Recruitment details
Participants with confirmed symptomatic deep vein thrombosis or pulmonary embolism, who either had been treated for 6 or 12 months with warfarin or acenocoumarol or rivaroxaban in study NCT00440193, or who had been treated for 6 to 14 months with warfarin or acenocoumarol outside study NCT00440193, were recruited at specialized study sites.
Pre-assignment details
Out of 1200 participants screened, 3 failed screening (2 due to withdrawal of consent and 1 due to a protocol violation), and 1197 participants were randomized (602 to rivaroxaban and 595 to placebo).
Participants by arm
| Arm | Count |
|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) Participants were to receive rivaroxaban 20 mg oral tablet once daily | 602 |
| Placebo Participants were to receive matching placebo oral tablet once daily | 594 |
| Total | 1,196 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Observational Period | Clinical endpoint reached | 3 | 1 |
| Observational Period | Death | 0 | 2 |
| Observational Period | Lost to Follow-up | 0 | 1 |
| Observational Period | Participant convenience | 1 | 0 |
| Observational Period | Study termination by sponsor | 1 | 1 |
| Observational Period | Technical problems | 1 | 0 |
| Observational Period | Withdrawal by Subject | 2 | 2 |
| Treatment Period | Adverse Event | 39 | 18 |
| Treatment Period | Clinical endpoint reached | 6 | 50 |
| Treatment Period | Death | 1 | 1 |
| Treatment Period | Lost to Follow-up | 1 | 1 |
| Treatment Period | Participant convenience | 1 | 0 |
| Treatment Period | Participant did not receive treatment | 4 | 4 |
| Treatment Period | Physician Decision | 1 | 1 |
| Treatment Period | Protocol driven decision point | 1 | 1 |
| Treatment Period | Protocol Violation | 2 | 1 |
| Treatment Period | Site closed by investigator | 1 | 2 |
| Treatment Period | Study terminated by sponsor | 156 | 148 |
| Treatment Period | Technical problems | 1 | 0 |
| Treatment Period | Withdrawal by Subject | 22 | 19 |
Baseline characteristics
| Characteristic | Rivaroxaban (Xarelto, BAY59-7939) | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 58.2 years STANDARD_DEVIATION 15.6 | 58.4 years STANDARD_DEVIATION 16 | 58.3 years STANDARD_DEVIATION 15.8 |
| Age, Customized 18 - 40 years | 87 participants | 94 participants | 181 participants |
| Age, Customized >40 - <65 years | 273 participants | 280 participants | 553 participants |
| Age, Customized 65 - 75 years | 153 participants | 121 participants | 274 participants |
| Age, Customized >75 years | 89 participants | 99 participants | 188 participants |
| Sex: Female, Male Female | 248 Participants | 255 Participants | 503 Participants |
| Sex: Female, Male Male | 354 Participants | 339 Participants | 693 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 63 / 598 | 65 / 590 |
| serious Total, serious adverse events | 59 / 598 | 52 / 590 |
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. For definition of DVT/PE, kindly refer to the link in the Protocol section.
Time frame: 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 | 1.3 Percentage of participants |
| Placebo | 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 | 7.1 Percentage of participants |
Comparison: The rivaroxaban to comparator hazard ratio was computed with a 95% CI (confidence interval) (two-sided testing).p-value: <0.000195% CI: [0.087, 0.393]Regression, Cox
Secondary
Percentage of Participants With All Death
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. Treatment-emergent events and all events post randomization were reported. Treatment-emergent: after intake of first tablet of study medication as randomized but not more than 2 days after stop of study medication (referred to as time window: 2 days)
Time frame: 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 study treatment. For this population, participants were analyzed according to the treatment they received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With All Death | Treatment-emergent (time window: 2 days) | 0.2 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With All Death | All post-randomization | 0.2 Percentage of participants |
| Placebo | Percentage of Participants With All Death | Treatment-emergent (time window: 2 days) | 0.2 Percentage of participants |
| Placebo | Percentage of Participants With All Death | All post-randomization | 0.3 Percentage of participants |
Secondary
Percentage of Participants With Clinically Relevant Bleeding
All events adjudicated/confirmed by CIAC blinded to treatment. Clinically relevant bleeding included major bleeding (definition: see outcome 7) 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 daily life activities. Treatment-emergent events (after intake of 1st study medication tablet as randomized up to 2 days after stop of study medication \['time window: 2 days'\]) and all events post randomization were reported
Time frame: 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 study treatment. For this population, participants were analyzed according to the treatment they received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Clinically Relevant Bleeding | Treatment-emergent (time window: 2 days) | 6.0 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Clinically Relevant Bleeding | All post-randomization | 6.0 Percentage of participants |
| Placebo | Percentage of Participants With Clinically Relevant Bleeding | Treatment-emergent (time window: 2 days) | 1.2 Percentage of participants |
| Placebo | Percentage of Participants With Clinically Relevant Bleeding | All post-randomization | 1.9 Percentage of participants |
Comparison: The rivaroxaban to comparator hazard ratio was computed with a 95% CI (two-sided testing), comparison was done for the treatment emergent (within two days after end of treatment) bleeding events.p-value: <0.000195% CI: [2.307, 11.652]Regression, Cox
Secondary
Percentage of Participants With Major Bleeding
All events were adjudicated and confirmed by a central independent adjudication committee (CIAC) blinded to treatment. Major bleeding event was overt bleeding associated with a 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. Treatment-emergent \[after intake of first tablet of study medication as randomized but not more than 2 days after stop of study medication (referred to as time window: 2 days)\] events and all events post randomization were reported.
Time frame: 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 study treatment. For this population, participants were analyzed according to the treatment they received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Major Bleeding | Treatment-emergent (time window: 2 days) | 0.7 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Major Bleeding | All post-randomization | 0.7 Percentage of participants |
| Placebo | Percentage of Participants With Major Bleeding | Treatment-emergent (time window: 2 days) | 0.0 Percentage of participants |
| Placebo | Percentage of Participants With Major Bleeding | All post-randomization | 0.2 Percentage of participants |
Comparison: The rivaroxaban to comparator hazard ratio was computed with a 95% CI (two-sided testing), comparison was done for the treatment emergent (within two days after end of treatment) bleeding events.p-value: 0.1121Log Rank
Secondary
Percentage of Participants With Net Clinical Benefit as Composite of Recurrent DVT or Non-fatal or Fatal PE and Major Bleeding Events 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: 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 Net Clinical Benefit as Composite of Recurrent DVT or Non-fatal or Fatal PE and Major Bleeding Events Until the Intended End of Study Treatment | 2.0 Percentage of participants |
| Placebo | Percentage of Participants With Net Clinical Benefit as Composite of Recurrent DVT or Non-fatal or Fatal PE and Major Bleeding Events Until the Intended End of Study Treatment | 7.1 Percentage of participants |
Comparison: The rivaroxaban to comparator hazard ratio was computed with a 95% CI (two-sided testing).p-value: <0.000195% CI: [0.146, 0.528]Regression, Cox
Secondary
Percentage of Participants With Other Vascular Events
All pre-defined vascular events (acute coronary syndromes, ischemic stroke, transient ischemic attack, non-central nervous system systemic embolism and vascular death) were adjudicated/confirmed by a central independent adjudication committee blinded to treatment, based on results/films/images of confirmatory testing, and/or case summaries. On treatment events and all events post randomization were reported. On treatment: after intake of first tablet of study medication as randomized but not more than 1 day after stop of study medication (referred to as time window: 1 day)
Time frame: 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 study treatment. For this population, participants were analyzed according to the treatment they received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Other Vascular Events | On treatment (time window: 1 day) | 0.5 Percentage of participants |
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Other Vascular Events | All post-randomization | 0.8 Percentage of participants |
| Placebo | Percentage of Participants With Other Vascular Events | On treatment (time window: 1 day) | 0.7 Percentage of participants |
| Placebo | Percentage of Participants With Other Vascular Events | All post-randomization | 0.7 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: 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 | 0.8 Percentage of participants |
| Placebo | Percentage of Participants With Recurrent DVT Until the Intended End of Study Treatment | 5.2 Percentage of participants |
Secondary
Percentage of Participants With Recurrent VTE (PE or 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 (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), results/films/images of confirmatory testing, and/or case summaries.
Time frame: 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 VTE (PE or DVT) Until the Intended End of Study Treatment | 1.2 Percentage of participants |
| Placebo | Percentage of Participants With Recurrent VTE (PE or DVT) Until the Intended End of Study Treatment | 7.1 Percentage of participants |
Secondary
Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE, All Cause Mortality, Strokes and Myocardial Infarctions 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), results/films/images of confirmatory testing, and/or case summaries.
Time frame: 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, All Cause Mortality, Strokes and Myocardial Infarctions Until the Intended End of Study Treatment | 1.5 Percentage of participants |
| Placebo | Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE, All Cause Mortality, Strokes and Myocardial Infarctions Until the Intended End of Study Treatment | 7.4 Percentage of participants |
Comparison: The rivaroxaban to comparator hazard ratio was computed with a 95% CI (two-sided testing).p-value: <0.000195% CI: [0.096, 0.405]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), or lung scintigraphy (for PE), and/or case summaries.
Time frame: 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 | 1.3 Percentage of participants |
| Placebo | Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality Until the Intended End of Study Treatment | 7.2 Percentage of participants |
Comparison: The rivaroxaban to comparator hazard ratio was computed with a 95% CI (two-sided testing).p-value: <0.000195% CI: [0.085, 0.383]Regression, Cox
Other Pre-specified
Percentage of Participants With Death (PE Cannot be Excluded) 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 unexplained death for which DVT/PE could not be ruled out, results/films/images of confirmatory testing, and/or case summaries.
Time frame: 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 Death (PE Cannot be Excluded) Until the Intended End of Study Treatment | 0.2 Percentage of participants |
| Placebo | Percentage of Participants With Death (PE Cannot be Excluded) Until the Intended End of Study Treatment | 0.0 Percentage of participants |
Other Pre-specified
Percentage of Participants With Death (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 autopsy, results/films/images of confirmatory testing, and/or case summaries.
Time frame: 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 Death (PE) Until the Intended End of Study Treatment | 0.0 Percentage of participants |
| Placebo | Percentage of Participants With Death (PE) Until the Intended End of Study Treatment | 0.2 Percentage of participants |
Other Pre-specified
Percentage of Participants With Net Clinical Benefit as Composite of Recurrent DVT or Non-fatal or Fatal PE and Major Bleeding Events During Observational Period
Events were adjudicated/confirmed by a central independent adjudication committee blinded to treatment, based on either compression ultrasound, venography, spiral CT 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 or more units, occurring in a critical site or contributing to death.
Time frame: 30 days observational period after last intake of study medication
Population: Intention-to-treat (ITT) population entering observational period. Participants were analyzed according to the treatment assigned at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Net Clinical Benefit as Composite of Recurrent DVT or Non-fatal or Fatal PE and Major Bleeding Events During Observational Period | 1.2 Percentage of participants |
| Placebo | Percentage of Participants With Net Clinical Benefit as Composite of Recurrent DVT or Non-fatal or Fatal PE and Major Bleeding Events During Observational Period | 0.9 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 or venography, results/films/images of confirmatory testing, and/or case summaries.
Time frame: 30 days observational period after last intake of study medication
Population: Intention-to-treat (ITT) population entering observational period. Participants were analyzed according to the treatment assigned at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Recurrent DVT During Observational Period | 0.9 Percentage of participants |
| Placebo | Percentage of Participants With Recurrent DVT During Observational Period | 0.7 Percentage of participants |
Other Pre-specified
Percentage of Participants With Recurrent VTE (PE or 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 (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), results/films/images of confirmatory testing, and/or case summaries.
Time frame: 30 days observational period after last intake of study medication
Population: Intention-to-treat (ITT) population entering observational period. Participants were analyzed according to the treatment assigned at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Recurrent VTE (PE or DVT) During Observational Period | 1.2 Percentage of participants |
| Placebo | Percentage of Participants With Recurrent VTE (PE or DVT) During Observational Period | 0.9 Percentage of participants |
Other Pre-specified
Percentage of Participants With Symptomatic Recurrent 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 spiral computed tomography (CT) scanning, pulmonary angiography, ventilation/perfusion lung scan, lung scintigraphy, results/films/images of confirmatory testing, and/or case summaries.
Time frame: 30 days observational period after last intake of study medication
Population: Intention-to-treat (ITT) population entering observational period. Participants were analyzed according to the treatment assigned at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Percentage of Participants With Symptomatic Recurrent PE During Observational Period | 0.3 Percentage of participants |
| Placebo | Percentage of Participants With Symptomatic Recurrent PE During Observational Period | 0.2 Percentage of participants |
Other Pre-specified
Percentage of Participants With Symptomatic 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 either spiral computed tomography (CT) scanning, pulmonary angiography, ventilation/perfusion lung scan, lung scintigraphy, results/films/images of confirmatory testing, and/or case summaries.
Time frame: 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 PE Until the Intended End of Study Treatment | 0.3 Percentage of participants |
| Placebo | Percentage of Participants With Symptomatic Recurrent PE Until the Intended End of Study Treatment | 2.2 Percentage of participants |
Other Pre-specified
Percentage of Participants With Symptomatic Recurrent Venous Thromboembolism [VTE] (i.e. the Composite of Recurrent Deep Vein Thrombosis [DVT] or Fatal or Non-fatal Pulmonary Embolism [PE]) During Observational Period
All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound (for DVT), venography (for DVT), spiral computed tomography (CT) scanning (for PE), pulmonary angiography (for PE), ventilation/perfusion lung scan (for PE), lung scintigraphy (for PE), autopsy (for fatal PE) or unexplained death for which DVT/PE could not be ruled out (for fatal PE), results/films/images of confirmatory testing, and/or case summaries.
Time frame: 30 days observational period after last intake of study medication
Population: Intention-to-treat (ITT) population entering observational period. 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]) During Observational Period | 1.2 Percentage of participants |
| Placebo | Percentage of Participants With Symptomatic Recurrent Venous Thromboembolism [VTE] (i.e. the Composite of Recurrent Deep Vein Thrombosis [DVT] or Fatal or Non-fatal Pulmonary Embolism [PE]) During Observational Period | 0.9 Percentage of participants |
Other Pre-specified
Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE, All Cause Mortality, Strokes and Myocardial Infarctions 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), results/films/images of confirmatory testing, and/or case summaries.
Time frame: 30 days observational period after last intake of study medication
Population: Intention-to-treat (ITT) population entering observational period. 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, All Cause Mortality, Strokes and Myocardial Infarctions During Observational Period | 1.4 Percentage of participants |
| Placebo | Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE, All Cause Mortality, Strokes and Myocardial Infarctions During Observational Period | 1.1 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: 30 days observational period after last intake of study medication
Population: Intention-to-treat (ITT) population entering observational period. 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 During Observational Period | 1.2 Percentage of participants |
| Placebo | Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality During Observational Period | 1.1 Percentage of participants |