(0.1%)
 0
 
Fatal PE/Death where PE cannot be ruled out
 4

(0.2%)
 6

(0.3%)
 
Major or clinically relevant non-major bleeding
 139

(8.1%)
 138

(8.1%)
 
Major bleeding events
 14

(0.8%)
 20

(1.2%)
 

a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily

b) Enoxaparin for at least 5 days, overlapped with and followed by VKA

* p < 0.0001 (non-inferiority to a prespecified hazard ratio of 2.0); hazard ratio: 0.680 (0.443 - 1.042), p=0.076 (superiority)

In the Einstein PE study (see Table 6) rivaroxaban was demonstrated to be non-inferior to enoxaparin/VKA for the primary efficacy outcome (p=0.0026 (test for non-inferiority); hazard ratio: 1.123 (0.749 – 1.684)). The prespecified net clinical benefit (primary efficacy outcome plus major bleeding events) was reported with a hazard ratio of 0.849 ((95% CI: 0.633 - 1.139), nominal p value p= 0.275). INR values were within the therapeutic range a mean of 63% of the time for the mean treatment duration of 215 days, and 57%, 62%, and 65% of the time in the 3-, 6-, and 12-month intended treatment duration groups, respectively. In the enoxaparin/VKA group, there was no clear relation between the level of mean centre TTR (Time in Target INR Range of 2.0 – 3.0) in the equally sized tertiles and the incidence of the recurrent VTE (p=0.082 for interaction). Within the highest tertile according to centre, the hazard ratio with rivaroxaban versus warfarin was 0.642 (95% CI: 0.277 - 1.484).

The incidence rates for the primary safety outcome (major or clinically relevant non-major bleeding events) were slightly lower in the rivaroxaban treatment group (10.3% (249/2412)) than in the enoxaparin/VKA treatment group (11.4% (274/2405)). The incidence of the secondary safety outcome (major bleeding events) was lower in the rivaroxaban group (1.1% (26/2412)) than in the enoxaparin/VKA group (2.2% (52/2405)) with a hazard ratio 0.493 (95% CI: 0.308 - 0.789).

Table 6: Efficacy and safety results from phase III Einstein PE
 
Study population
 4,832 patients with an acute symptomatic PE
 
Treatment dosage and duration
 Xareltoa)

3, 6 or 12 months

N=2,419
 Enoxaparin/VKAb)

3, 6 or 12 months

N=2,413
 
Symptomatic recurrent VTE*
 50

(2.1%)
 44

(1.8%)
 
Symptomatic recurrent PE
 23

(1.0%)
 20

(0.8%)
 
Symptomatic recurrent DVT
 18

(0.7%)
 17

(0.7%)
 
Symptomatic PE and DVT
 0
 2

(<0.1%)
 
Fatal PE/Death where PE cannot be ruled out
 11

(0.5%)
 7

(0.3%)
 
Major or clinically relevant non-major bleeding
 249

(10.3%)
 274

(11.4%)
 
Major bleeding events
 26

(1.1%)
 52

(2.2%)
 

a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily

b) Enoxaparin for at least 5 days, overlapped with and followed by VKA

* p < 0.0026 (non-inferiority to a prespecified hazard ratio of 2.0); hazard ratio: 1.123 (0.749 – 1.684)

A prespecified pooled analysis of the outcome of the Einstein DVT and PE studies was conducted (see Table 7).

T