Xarelto (Page 11 of 18)

14.3 Reduction in the Risk of Recurrence of DVT and/or PE

EINSTEIN CHOICE Study

XARELTO for reduction in the risk of recurrence of DVT and of PE was evaluated in the EINSTEIN CHOICE study [NCT02064439], a multi-national, double-blind, superiority study comparing XARELTO (10 or 20 mg once daily with food) to 100 mg acetylsalicylic acid (aspirin) once daily in patients who had completed 6 to 12 months of anticoagulant treatment for DVT and/or PE following the acute event. The intended treatment duration in the study was up to 12 months. Patients with an indication for continued therapeutic-dose anticoagulation were excluded.

Because the benefit-risk assessment favored the 10 mg dose versus aspirin compared to the 20 mg dose versus aspirin, only the data concerning the 10 mg dose is discussed below.

A total of 2275 patients were randomized and followed on study treatment for a mean of 290 days for the XARELTO and aspirin treatment groups. The mean age was approximately 59 years. The population was 56% male, 70% Caucasian, 14% Asian and 3% Black. In the EINSTEIN CHOICE study, 51% of patients had DVT only, 33% had PE only, and 16% had PE and DVT combined. Other risk factors included idiopathic VTE (43%), previous episode of DVT/PE (17%), recent surgery or trauma (12%), prolonged immobilization (10%), use of estrogen containing drugs (5%), known thrombophilic conditions (6%), Factor V Leiden gene mutation (4%), or active cancer (3%).

In the EINSTEIN CHOICE study, XARELTO 10 mg was demonstrated to be superior to aspirin 100 mg for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE.

Table 21 displays the overall results for the primary composite endpoint and its components.

Table 21: Primary Composite Endpoint and its Components Results * in EINSTEIN CHOICE Study – Full Analysis Set
EventXARELTO 10 mg N=1,127 n (%) Acetylsalicylic Acid (Aspirin) 100 mg N=1,131 n (%) XARELTO 10 mg vs. Aspirin 100 mg Hazard Ratio (95% CI)
*
For the primary efficacy analysis, all confirmed events were considered from randomization up to the end of intended treatment duration (12 months) irrespective of the actual treatment duration. The individual component of the primary endpoint represents the first occurrence of the event.
Primary Composite Endpoint13 (1.2)50 (4.4)0.26 (0.14, 0.47) p<0.0001
Symptomatic recurrent DVT8 (0.7)29 (2.6)
Symptomatic recurrent PE5 (0.4)19 (1.7)
Death (PE)01 (<0.1)
Death (PE cannot be excluded)01 (<0.1)

Figure 8 is a plot of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups.

Figure 8: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Full Analysis Set) – EINSTEIN CHOICE Study

Figure 8
(click image for full-size original)

14.4 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery

XARELTO was studied in 9011 patients (4487 XARELTO-treated, 4524 enoxaparin-treated patients) in the REgulation of Coagulation in ORthopedic Surgery to Prevent DVT and PE, Controlled, Double-blind, Randomized Study of BAY 59-7939 in the Extended Prevention of VTE in Patients Undergoing Elective Total Hip or Knee Replacement (RECORD 1, 2, and 3) [NCT00329628, NCT00332020, NCT00361894] studies.

The two randomized, double-blind, clinical studies (RECORD 1 and 2) in patients undergoing elective total hip replacement surgery compared XARELTO 10 mg once daily starting at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin 40 mg once daily started 12 hours preoperatively. In RECORD 1 and 2, a total of 6727 patients were randomized and 6579 received study drug. The mean age [± standard deviation (SD)] was 63 ± 12.2 (range 18 to 93) years with 49% of patients ≥65 years and 55% of patients were female. More than 82% of patients were White, 7% were Asian, and less than 2% were Black. The studies excluded patients undergoing staged bilateral total hip replacement, patients with severe renal impairment defined as an estimated creatinine clearance <30 mL/min, or patients with significant liver disease (hepatitis or cirrhosis). In RECORD 1, the mean exposure duration (± SD) to active XARELTO and enoxaparin was 33.3 ± 7.0 and 33.6 ± 8.3 days, respectively. In RECORD 2, the mean exposure duration to active XARELTO and enoxaparin was 33.5 ± 6.9 and 12.4 ± 2.9 days, respectively. After Day 13, oral placebo was continued in the enoxaparin group for the remainder of the double-blind study duration. The efficacy data for RECORD 1 and 2 are provided in Table 22.

Table 22: Summary of Key Efficacy Analysis Results for Patients Undergoing Total Hip Replacement Surgery — Modified Intent-to-Treat Population
RECORD 1 RECORD 2
Treatment Dosage and Duration XARELTO 10 mg once daily Enoxaparin 40 mg once daily RRR *, p-value XARELTO 10 mg once daily Enoxaparin 40 mg once daily RRR *, p-value
*
Relative Risk Reduction; CI = confidence interval
Includes the placebo-controlled period of RECORD 2
Proximal DVT, nonfatal PE or VTE-related death
Number of Patients N=1513 N=1473 N=834 N=835
Total VTE 17 (1.1%) 57 (3.9%) 71% (95% CI: 50, 83), p<0.001 17 (2.0%) 70 (8.4%) 76% (95% CI: 59, 86), p<0.001
Components of Total VTE
Proximal DVT 1 (0.1%) 31 (2.1%) 5 (0.6%) 40 (4.8%)
Distal DVT 12 (0.8%) 26 (1.8%) 11 (1.3%) 43 (5.2%)
Non-fatal PE 3 (0.2%) 1 (0.1%) 1 (0.1%) 4 (0.5%)
Death (any cause) 4 (0.3%) 4 (0.3%) 2 (0.2%) 4 (0.5%)
Number of Patients N=1600 N=1587 N=928 N=929
Major VTE 3 (0.2%) 33 (2.1%) 91% (95% CI: 71, 97), p<0.001 6 (0.7%) 45 (4.8%) 87% (95% CI: 69, 94), p<0.001
Number of Patients N=2103 N=2119 N=1178 N=1179
Symptomatic VTE 5 (0.2%) 11 (0.5%) 3 (0.3%) 15 (1.3%)

One randomized, double-blind, clinical study (RECORD 3) in patients undergoing elective total knee replacement surgery compared XARELTO 10 mg once daily started at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin. In RECORD 3, the enoxaparin regimen was 40 mg once daily started 12 hours preoperatively. The mean age (± SD) of patients in the study was 68 ± 9.0 (range 28 to 91) years with 66% of patients ≥65 years. Sixty-eight percent (68%) of patients were female. Eighty-one percent (81%) of patients were White, less than 7% were Asian, and less than 2% were Black. The study excluded patients with severe renal impairment defined as an estimated creatinine clearance <30 mL/min or patients with significant liver disease (hepatitis or cirrhosis). The mean exposure duration (± SD) to active XARELTO and enoxaparin was 11.9 ± 2.3 and 12.5 ± 3.0 days, respectively. The efficacy data are provided in Table 23.

Table 23: Summary of Key Efficacy Analysis Results for Patients Undergoing Total Knee Replacement Surgery — Modified Intent-to-Treat Population
RECORD 3
Treatment Dosage and Duration XARELTO 10 mg once daily Enoxaparin 40 mg once daily RRR *, p-value
*
Relative Risk Reduction; CI = confidence interval
Proximal DVT, nonfatal PE or VTE-related death
Number of Patients N=813 N=871
Total VTE 79 (9.7%) 164 (18.8%) 48% (95% CI: 34, 60), p<0.001
Components of events contributing to Total VTE
Proximal DVT 9 (1.1%) 19 (2.2%)
Distal DVT 74 (9.1%) 154 (17.7%)
Non-fatal PE 0 4 (0.5%)
Death (any cause) 0 2 (0.2%)
Number of Patients N=895 N=917
Major VTE 9 (1.0%) 23 (2.5%) 60% (95% CI: 14, 81), p = 0.024
Number of Patients N=1206 N=1226
Symptomatic VTE 8 (0.7%) 24 (2.0%)

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