results of the phase II bid studies showed that total daily doses of 5 20 mg rivaroxaban warranted further investigation, while the od study demonstrated that a 10 mg once daily dose of rivaroxaban provided the optimum balance between effi cacy and safety. Based on these fi ndings, a once daily 10 mg dose of rivaroxaban was evaluated in phase III studies. The RECORD1 trial compared extended GSK1904529A prophylaxis with rivaroxaban with extended enoxaparin after THR. Patients received either oral rivaroxaban, started 6 8 hours after surgery for 35 �? days, or subcutaneous enoxaparin, started the evening before surgery. In this study, the criteria for non inferiority of rivaroxaban vs enoxaparin were met and testing for superiority was performed.
The primary effi cacy outcome occurred Regorafenib in 18/1595 of patients treated with rivaroxaban compared with 58/1558 of those receiving enoxaparin, demonstrating a relative risk reduction of 70%. The incidence of major bleeding was similar in both groups . In RECORD2, extended prophylaxis with rivaroxaban was compared with short term enoxaparin followed by placebo for prevention of VTE after THR in 2509 patients. Patients received subcutaneous enoxaparin 40 mg od, beginning the evening before surgery, continuing for 10 14 days, and followed by placebo until day 35 �?, or oral rivaroxaban 10 mg od beginning 6 8 hours after surgery and continuing for 35 �? days. The primary efficacy outcome occurred in 17/864 of patients given extended prophylaxis with rivaroxaban compared with 81/869 of patients given short term prophylaxis with enoxaparin, demonstrating an RRR of 79%.
The rate of major bleeding was low and similar in those receiving extended prophylaxis with rivaroxaban and short term enoxaparin . The RECORD3 trial evaluated oral rivaroxaban compared with subcutaneous enoxaparin for the prevention of VTE after TKR in 2531 patients. The primary effi cacy outcome occurred in 79/824 of patients receiving rivaroxaban compared with 166/878 of those receiving enoxaparin, demonstrating an RRR of 49%. Major bleeding occurred in 7/1220 administered rivaroxaban and 6/1239 of patients administered enoxaparin . RECORD4 compared once daily oral rivaroxaban with twice daily subcutaneous enoxaparin for VTE prophylaxis after TKR in 3148 randomized patients. The primary effi cacy outcome was the same as for RECORD3 and occurred in signifi cantly fewer patients in the rivaroxaban group.
The rate of major bleeding was similar in the rivaroxaban and enoxaparin groups. Rivaroxaban was also evaluated for VTE treatment in the phase II EINSTEIN DVT and ODIXa DVT trials. In these doseranging studies, both od and bid rivaroxaban dosing had similar effi cacy to standard enoxaparin. In addition, a low rate of bleeding was observed with all rivaroxaban doses, suggesting that long term treatment with rivaroxaban could be possible. In the ODIXa DVT study, the doses of rivaroxaban selected for evaluation were based on pharmacokinetic and pharmacodynamic analyses, as well as results of VTE prevention trials in which a 10 mg od dose appeared to be optimal for treatment of established thrombosis, a minimum of two times the prophylactic dose was considered appropriate. In combination with results of the EINSTEIN DVT study, where 20 40 mg od doses of rivaroxaban were evaluated, the lowest dose of rivaroxaban was chosen for evaluation in phase III clinical trials. In summary, extended prophylaxis with rivaroxaban not only demonstrated non inferiority,