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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
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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
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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 
Overall Participants Analyzed 
[Units: Participants]
 2419   2413   4832 
Age [1] 
[Units: Years]
Mean (Standard Deviation)
 57.9  (17.3)   57.5  (17.2)   57.7  (17.3) 
[1] Intention-to-treat (ITT) population
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 
[1] Intention-to-treat (ITT) population
Gender [1] 
[Units: Participants]
     
Female   1309   1247   2556 
Male   1110   1166   2276 
[1] Intention-to-treat (ITT) population


  Outcome Measures
  Show 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 ]

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 ]

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 ]
  Hide Outcome Measure 3

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 
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 ]

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 ]

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 ]

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

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 ]

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 ]

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 ]

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 ]

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 ]

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 ]

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 ]

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 ]

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 ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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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
No text entered.


  More Information