Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism - The EINSTEIN PE Study

This study has been completed.
Sponsor:
Collaborator:
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Information provided by (Responsible Party):
Bayer
ClinicalTrials.gov Identifier:
NCT00439777
First received: February 23, 2007
Last updated: January 25, 2014
Last verified: January 2014
Results First Received: November 22, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Pulmonary Embolism
Interventions: Drug: Rivaroxaban (Xarelto, BAY59-7939)
Drug: Enoxaparin overlapping with and followed by VKA

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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).

Reporting Groups
  Description
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.)
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)

Participant Flow for 2 periods

Period 1:   Treatment Period
    Rivaroxaban (Xarelto, BAY59-7939)     Enoxaparin/VKA  
STARTED     2420     2413  
Participants Received Treatment     2412     2405  
COMPLETED     2001     1954  
NOT COMPLETED     419     459  
Death                 29                 21  
Study terminated by sponsor                 125                 132  
Site closed by investigator                 0                 1  
Did not take study treatment                 7                 8  
Adverse Event                 111                 92  
Protocol Violation                 23                 30  
Withdrawal by Subject                 66                 118  
Lack of Efficacy                 1                 4  
Lost to Follow-up                 8                 10  
Protocol driven decision point                 1                 3  
Physician Decision                 7                 18  
Clinical endpoint reached                 26                 13  
Technical problems                 3                 1  
Participant convenience                 12                 8  

Period 2:   Observational Period
    Rivaroxaban (Xarelto, BAY59-7939)     Enoxaparin/VKA  
STARTED     2206 [1]   2197 [1]
COMPLETED     2165     2156  
NOT COMPLETED     41     41  
Protocol Violation                 0                 2  
Withdrawal by Subject                 9                 5  
Lost to Follow-up                 1                 11  
Death                 27                 20  
Study terminated by sponsor                 3                 1  
Protocol driven decision point                 0                 1  
Lack of Efficacy                 1                 0  
Technical problems                 0                 1  
[1] All participants who took any study medication and entered the observational period.



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
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.)
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)
Total Total of all reporting groups

Baseline Measures
    Rivaroxaban (Xarelto, BAY59-7939)     Enoxaparin/VKA     Total  
Number of Participants  
[units: participants]
  2419     2413     4832  
Age [1]
[units: Years]
Mean ± Standard Deviation
  57.9  ± 17.3     57.5  ± 17.2     57.7  ± 17.3  
Age, Customized [1]
[units: Participants]
     
18 - < 40 years     410     432     842  
40 - < 60 years     794     779     1573  
60 - < 75 years     740     754     1494  
≥ 75 years     475     448     923  
Gender [1]
[units: Participants]
     
Female     1309     1247     2556  
Male     1110     1166     2276  
[1] Intention-to-treat (ITT) population



  Outcome Measures
  Hide All Outcome Measures

1.  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   [ Time Frame: 3-, 6-, or 12-month study treatment period ]

Measure Type Primary
Measure Title Percentage of Participants With Symptomatic Recurrent Venous Thromboembolism [VTE] (i.e. the Composite of Recurrent Deep Vein Thrombosis [DVT] or Fatal or Non-fatal Pulmonary Embolism [PE]) Until the Intended End of Study Treatment
Measure Description All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound (for DVT), venography (for DVT), spiral computed tomography (CT) scanning (for PE), pulmonary angiography (for PE), ventilation/perfusion lung scan (for PE), lung scintigraphy (for PE), autopsy (for fatal PE) or unexplained death for which DVT/PE could not be ruled out (for fatal PE), and/or case summaries.
Time Frame 3-, 6-, or 12-month study treatment period  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.)
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)

Measured Values
    Rivaroxaban (Xarelto, BAY59-7939)     Enoxaparin/VKA  
Number of Participants Analyzed  
[units: participants]
  2419     2413  
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  
[units: Percentage of participants]
  2.1     1.8  


Statistical Analysis 1 for 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
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Regression, Cox
P Value [4] 0.0026
Hazard Ratio (HR) [5] 1.12
Standard Error of the mean ± 0.2067
95% Confidence Interval ( 0.75 to 1.68 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Assuming equal efficacy, a total of 88 events will give a power of 90% to demonstrate that rivaroxaban is at least as effective as the comparator, considering a relative non-inferiority upper CI margin for the hazard ratio of 2.0 (two-sided alpha=0.05). The mean overall incidence for the primary efficacy outcome of 3% was expected and therefore 1465 patients per group would be needed. This number was to be adjusted based on the observed overall incidence of symptomatic recurrent VTE.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  Stratified by intend treatment duration, adjusted for presence of active malignancy at baseline
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  The standard error of the log hazard ratio was estimated.



2.  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   [ Time Frame: 3-, 6-, or 12-month study treatment period ]

Measure Type Secondary
Measure Title Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality Until the Intended End of Study Treatment
Measure Description All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound (for DVT), venography (for DVT), spiral computed tomography (CT) scanning (for PE), pulmonary angiography (for PE), ventilation/perfusion lung scan (for PE), lung scintigraphy (for PE), autopsy (for deaths), results/films/images of confirmatory testing, and/or case summaries.
Time Frame 3-, 6-, or 12-month study treatment period  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.)
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)

Measured Values
    Rivaroxaban (Xarelto, BAY59-7939)     Enoxaparin/VKA  
Number of Participants Analyzed  
[units: participants]
  2419     2413  
Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality Until the Intended End of Study Treatment  
[units: Percentage of participants]
  4.0     3.4  


Statistical Analysis 1 for Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality Until the Intended End of Study Treatment
Groups [1] All groups
Method [2] Regression, Cox
P Value [3] 0.33
Hazard Ratio (HR) [4] 1.16
Standard Error of the mean ± 0.1500
95% Confidence Interval ( 0.86 to 1.56 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Stratified by intend treatment duration, adjusted for presence of active malignancy at baseline.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Nominal p-value
[4] Other relevant estimation information:
  The standard error of the log hazard ratio was estimated.



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

Measure Type Secondary
Measure Title Percentage of Participants With an Event for Net Clinical Benefit 1 Until the Intended End of Study Treatment
Measure Description Net clinical benefit 1: composite of recurrent DVT or non-fatal or fatal PE, and major bleeding. Major bleeding was overt bleeding associated with 2 g/dL or greater fall in hemoglobin, leading to a transfusion of ≥2 units, occurring in a critical site or contributing to death. Net clinical benefit was considered greater in those participants with fewer composite events. All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment, based on either compression ultrasound, venography, spiral computed tomography scanning, pulmonary angiography, ventilation/perfusion lung scan, lung scintigraphy, autopsy or unexplained death for which DVT/PE could not be ruled out, results/films/images of confirmatory testing, and/or case summaries.
Time Frame 3-, 6-, or 12-month study treatment period  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.)
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)

Measured Values
    Rivaroxaban (Xarelto, BAY59-7939)     Enoxaparin/VKA  
Number of Participants Analyzed  
[units: participants]
  2419     2413  
Percentage of Participants With an Event for Net Clinical Benefit 1 Until the Intended End of Study Treatment  
[units: Percentage of participants]
  3.4     4.0  


Statistical Analysis 1 for Percentage of Participants With an Event for Net Clinical Benefit 1 Until the Intended End of Study Treatment
Groups [1] All groups
Method [2] Regression, Cox
P Value [3] 0.275
Hazard Ratio (HR) [4] 0.85
Standard Error of the mean ± 0.1499
95% Confidence Interval ( 0.63 to 1.14 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Stratified by intend treatment duration, adjusted for presence of active malignancy at baseline
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Nominal p-value
[4] Other relevant estimation information:
  The standard error of the log hazard ratio was estimated.



4.  Secondary:   Percentage of Participants With Recurrent PE Until the Intended End of Study Treatment   [ Time Frame: 3-, 6- or 12-month study treatment period ]

Measure Type Secondary
Measure Title Percentage of Participants With Recurrent PE Until the Intended End of Study Treatment
Measure Description 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.)
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)

Measured Values
    Rivaroxaban (Xarelto, BAY59-7939)     Enoxaparin/VKA  
Number of Participants Analyzed  
[units: participants]
  2419     2413  
Percentage of Participants With Recurrent PE Until the Intended End of Study Treatment  
[units: Percentage of participants]
  1.4     1.2  


Statistical Analysis 1 for Percentage of Participants With Recurrent PE Until the Intended End of Study Treatment
Groups [1] All groups
Method [2] Regression, Cox
P Value [3] 0.55
Hazard Ratio (HR) [4] 1.16
Standard Error of the mean ± 0.2570
95% Confidence Interval ( 0.70 to 1.93 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Stratified by intend treatment duration, adjusted for presence of active malignancy at baseline.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  nominal p-value
[4] Other relevant estimation information:
  The standard error of the log hazard ratio was estimated.



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

Measure Type Secondary
Measure Title Percentage of Participants With Recurrent DVT Until the Intended End of Study Treatment
Measure Description All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound, venography, results/films/images of confirmatory testing, and/or case summaries.
Time Frame 3-, 6- or 12-month study treatment period  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.)
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)

Measured Values
    Rivaroxaban (Xarelto, BAY59-7939)     Enoxaparin/VKA  
Number of Participants Analyzed  
[units: participants]
  2419     2413  
Percentage of Participants With Recurrent DVT Until the Intended End of Study Treatment  
[units: Percentage of participants]
  0.7     0.8  


Statistical Analysis 1 for Percentage of Participants With Recurrent DVT Until the Intended End of Study Treatment
Groups [1] All groups
Method [2] Regression, Cox
P Value [3] 0.85
Hazard Ratio (HR) [4] 0.94
Standard Error of the mean ± 0.3289
95% Confidence Interval ( 0.49 to 1.79 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Stratified by intend treatment duration, adjusted for presence of active malignancy at baseline.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Nominal p-value
[4] Other relevant estimation information:
  The standard error of the log hazard ratio was estimated.



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

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

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.)
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)

Measured Values
    Rivaroxaban (Xarelto, BAY59-7939)     Enoxaparin/VKA  
Number of Participants Analyzed  
[units: participants]
  2412     2405  
Percentage of Participants With Clinically Relevant Bleeding, Treatment-emergent (Time Window: Until 2 Days After Last Dose)  
[units: Percentage of participants]
  10.3     11.4  


Statistical Analysis 1 for Percentage of Participants With Clinically Relevant Bleeding, Treatment-emergent (Time Window: Until 2 Days After Last Dose)
Groups [1] All groups
Method [2] Regression, Cox
P Value [3] 0.23
Hazard Ratio (HR) [4] 0.90
Standard Error of the mean ± 0.08756
95% Confidence Interval ( 0.76 to 1.07 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Stratified by intend treatment duration, adjusted for presence of active malignancy at baseline.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  If the primary efficacy analysis shows that rivaroxaban is non-inferior to the comparator, the principal safety outcome was to be compared between treatment groups to maintain the overall type I error of 0.05 (2-sided) (a closed testing procedure).
[4] Other relevant estimation information:
  The standard error of the log hazard ratio was estimated.



7.  Secondary:   Percentage of Participants With All Deaths   [ Time Frame: 3-, 6- or 12-month study treatment period ]

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

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.)
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)

Measured Values
    Rivaroxaban (Xarelto, BAY59-7939)     Enoxaparin/VKA  
Number of Participants Analyzed  
[units: participants]
  2412     2405  
Percentage of Participants With All Deaths  
[units: Percentage of participants]
   
All post-randomization     2.6     2.1  
Treatment-emergent (time window: 2 days)     1.2     0.8  
Treatment-emergent (time window: 7 days)     1.5     1.1  

No statistical analysis provided for Percentage of Participants With All Deaths



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

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

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.)
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)

Measured Values
    Rivaroxaban (Xarelto, BAY59-7939)     Enoxaparin/VKA  
Number of Participants Analyzed  
[units: participants]
  2412     2405  
Percentage of Participants With Other Vascular Events, On-treatment (Time Window: Until 1 Day After Last Dose)  
[units: Percentage of participants]
  1.5     1.5  

No statistical analysis provided for Percentage of Participants With Other Vascular Events, On-treatment (Time Window: Until 1 Day After Last Dose)



9.  Other Pre-specified:   Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment   [ Time Frame: 3-, 6- or 12-month study treatment period ]

Measure Type Other Pre-specified
Measure Title Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment
Measure Description All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment, based on either compression ultrasound, venography, spiral computed tomography scanning, pulmonary angiography, ventilation/perfusion lung scan, lung scintigraphy, autopsy or unexplained death for which DVT/PE could not be ruled out, results/films/images of confirmatory testing, and/or case summaries. Major bleeding was overt bleeding associated with 2 g/dL or greater fall in hemoglobin, leading to a transfusion of ≥2 units, occurring in a critical site or contributing to death.
Time Frame 3-, 6- or 12-month study treatment period  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.)
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)

Measured Values
    Rivaroxaban (Xarelto, BAY59-7939)     Enoxaparin/VKA  
Number of Participants Analyzed  
[units: participants]
  2419     2413  
Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment  
[units: Percentage of participants]
   
Death (PE)     0.1     0.04  
Death (PE cannot be excluded)     0.3     0.2  
Symptomatic PE and DVT     0.0     0.1  
Symptomatic recurrent PE only     1.0     0.8  
Symptomatic recurrent DVT only     0.7     0.7  
Death (bleeding)     0.2     0.2  
Death (cardiovascular)     0.4     0.1  
Death (other)     1.3     1.5  
Major bleeding     1.4     2.4  

No statistical analysis provided for Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment



10.  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   [ Time Frame: Up to 30 days after the last intake of study medication ]

Measure Type Other Pre-specified
Measure Title Percentage of Participants With Symptomatic Recurrent VTE (i.e. the Composite of Recurrent DVT or Fatal or Non-fatal PE) During Observational Period
Measure Description All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound (for DVT), venography (for DVT), spiral computed tomography (CT) scanning (for PE), pulmonary angiography (for PE), ventilation/perfusion lung scan (for PE), lung scintigraphy (for PE), autopsy (for fatal PE) or unexplained death for which DVT/PE could not be ruled out (for fatal PE), and/or case summaries.
Time Frame Up to 30 days after the last intake of study medication  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.)
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)

Measured Values
    Rivaroxaban (Xarelto, BAY59-7939)     Enoxaparin/VKA  
Number of Participants Analyzed  
[units: participants]
  2211     2201  
Percentage of Participants With Symptomatic Recurrent VTE (i.e. the Composite of Recurrent DVT or Fatal or Non-fatal PE) During Observational Period  
[units: Percentage of participants]
  0.9     0.7  

No statistical analysis provided for Percentage of Participants With Symptomatic Recurrent VTE (i.e. the Composite of Recurrent DVT or Fatal or Non-fatal PE) During Observational Period



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

Measure Type Other Pre-specified
Measure Title Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality During Observational Period
Measure Description All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound (for DVT), venography (for DVT), spiral computed tomography (CT) scanning (for PE), pulmonary angiography (for PE), ventilation/perfusion lung scan (for PE), lung scintigraphy (for PE), autopsy (for deaths), results/films/images of confirmatory testing, and/or case summaries.
Time Frame Up to 30 days after the last intake of study medication  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.)
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)

Measured Values
    Rivaroxaban (Xarelto, BAY59-7939)     Enoxaparin/VKA  
Number of Participants Analyzed  
[units: participants]
  2213     2203  
Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality During Observational Period  
[units: Percentage of participants]
  2.1     1.5  

No statistical analysis provided for Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality During Observational Period



12.  Other Pre-specified:   Percentage of Participants With an Event for Net Clinical Benefit 1 During Observational Period   [ Time Frame: Up to 30 days after the last intake of study medication ]

Measure Type Other Pre-specified
Measure Title Percentage of Participants With an Event for Net Clinical Benefit 1 During Observational Period
Measure Description Net clinical benefit 1: composite of recurrent DVT or non-fatal or fatal PE, and major bleeding. Major bleeding was overt bleeding associated with 2 g/dL or greater fall in hemoglobin, leading to a transfusion of ≥2 units, occurring in a critical site or contributing to death. Net clinical benefit was considered greater in those participants with fewer composite events. All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment, based on either compression ultrasound, venography, spiral computed tomography scanning, pulmonary angiography, ventilation/perfusion lung scan, lung scintigraphy, autopsy or unexplained death for which DVT/PE could not be ruled out, results/films/images of confirmatory testing, and/or case summaries.
Time Frame Up to 30 days after the last intake of study medication  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.)
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)

Measured Values
    Rivaroxaban (Xarelto, BAY59-7939)     Enoxaparin/VKA  
Number of Participants Analyzed  
[units: participants]
  2212     2201  
Percentage of Participants With an Event for Net Clinical Benefit 1 During Observational Period  
[units: Percentage of participants]
  1.2     1.2  

No statistical analysis provided for Percentage of Participants With an Event for Net Clinical Benefit 1 During Observational Period



13.  Other Pre-specified:   Percentage of Participants With Recurrent DVT During Observational Period   [ Time Frame: Up to 30 days after the last intake of study medication ]

Measure Type Other Pre-specified
Measure Title Percentage of Participants With Recurrent DVT During Observational Period
Measure Description All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound, venography, results/films/images of confirmatory testing, and/or case summaries.
Time Frame Up to 30 days after the last intake of study medication  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.)
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)

Measured Values
    Rivaroxaban (Xarelto, BAY59-7939)     Enoxaparin/VKA  
Number of Participants Analyzed  
[units: participants]
  2210     2201  
Percentage of Participants With Recurrent DVT During Observational Period  
[units: Percentage of participants]
  0.3     0.1  

No statistical analysis provided for Percentage of Participants With Recurrent DVT During Observational Period



14.  Other Pre-specified:   Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period   [ Time Frame: Up to 30 days after the last intake of study medication ]

Measure Type Other Pre-specified
Measure Title Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period
Measure Description All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment, based on either compression ultrasound, venography, spiral computed tomography scanning, pulmonary angiography, ventilation/perfusion lung scan, lung scintigraphy, autopsy or unexplained death for which DVT/PE could not be ruled out, results/films/images of confirmatory testing, and/or case summaries. Major bleeding was overt bleeding associated with 2 g/dL or greater fall in hemoglobin, leading to a transfusion of ≥2 units, occurring in a critical site or contributing to death.
Time Frame Up to 30 days after the last intake of study medication  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.)
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)

Measured Values
    Rivaroxaban (Xarelto, BAY59-7939)     Enoxaparin/VKA  
Number of Participants Analyzed  
[units: participants]
  2213     2203  
Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period  
[units: Percentage of participants]
   
Death (PE)     0.09     0  
Death (PE cannot be excluded)     0     0.05  
Symptomatic PE and DVT     0.09     0  
Symptomatic recurrent PE only     0.5     0.5  
Symptomatic recurrent DVT only     0.2     0.1  
Death (bleeding)     0.09     0.09  
Death (cardiovascular)     0.3     0.05  
Death (other)     0.8     0.7  
Major bleeding     0.3     0.5  

No statistical analysis provided for Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period



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

Measure Type Post-Hoc
Measure Title Percentage of Participants With an Event for Net Clinical Benefit 2 Until the Intended End of Study Treatment
Measure Description 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.)
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)

Measured Values
    Rivaroxaban (Xarelto, BAY59-7939)     Enoxaparin/VKA  
Number of Participants Analyzed  
[units: participants]
  2419     2413  
Percentage of Participants With an Event for Net Clinical Benefit 2 Until the Intended End of Study Treatment  
[units: Percentage of participants]
  4.5     4.8  

No statistical analysis provided for Percentage of Participants With an Event for Net Clinical Benefit 2 Until the Intended End of Study Treatment



16.  Post-Hoc:   Percentage of Participants With an Event for Net Clinical Benefit 2 During Observational Period   [ Time Frame: Up to 30 days after the last intake of study medication ]

Measure Type Post-Hoc
Measure Title Percentage of Participants With an Event for Net Clinical Benefit 2 During Observational Period
Measure Description 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.)
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)

Measured Values
    Rivaroxaban (Xarelto, BAY59-7939)     Enoxaparin/VKA  
Number of Participants Analyzed  
[units: participants]
  2213     2201  
Percentage of Participants With an Event for Net Clinical Benefit 2 During Observational Period  
[units: Percentage of participants]
  1.5     1.4  

No statistical analysis provided for Percentage of Participants With an Event for Net Clinical Benefit 2 During Observational Period




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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