atran 150 and 220 mg and 1.4% for enoxaparin. In a BSI-201 Iniparib pooled analysis of the RE MODEL, RE MOBILIZE, and RE NOVATE studies, major VTE and VTE related death occurred in 3.3% of the enoxaparin group versus 3.0% of the dabigatran etexilate 220 mg group and 3.8% of the dabigatran etexilate 150 mg group. Major bleeding events were infrequent, and occurred at similar rates across all groups: enoxaparin 1.4%, dabigatran etexilate 220 mg 1.4%, and dabigatran etexilate 150 mg 1.1%. In summary, dabigatran has demonstrated non inferiority and a similar safety profi le to enoxaparin for VTE prevention after THR, and represents a viable, orally administered alternative to enoxaparin in this setting. The results for VTE prevention after TKR are less conclusive.
Dabigatran demonstrated non inferiority to enoxaparin in one phase III study but not in another, although it should be noted that different enoxaparin BIIB021 dosing regimens were used in each of these studies, bleeding rates with dabigatran were similar to enoxaparin in both studies. Based on the results of phase III studies, dabigatran has recently been approved in the European Union for the prevention of VTE following major orthopaedic surgery in adults. Dabigatran is currently being investigated in three further phase III trials: RE LY, a study comparing the effi cacy and safety of dabigatran with warfarin for the prevention of stroke and systemic embolism in patients with non valvular AF, RE COVER, a randomized study comparing the effi cacy and safety of dabigatran etexilate with warfarin for the treatment of acute symptomatic VTE, following initial treatment with a parenteral anticoagulant, and RE MEDY, a randomized, active controlled study to evaluate the effi cacy and safety of oral dabigatran etexilate compared with warfarin, for the secondary prevention of VTE.
Rivaroxaban Rivaroxaban is a once daily, oral, direct FXa inhibitor. It selectively and competitively binds to FXa with 1:1 stoichiometry, blocking the interaction of FXa with its substrate prothrombin. Rivaroxaban binds to the active site of FXa, its chlorothiophene moiety directed into the S1 pocket, and does not require highly basic groups like amidines for FXa affi nity. Binding inhibits not only free FXa but also fi brin bound FXa and prothrombinase activity. Rivaroxaban has high bioavailability and a dual mode of elimination, with one third of the dose excreted unchanged via the kidneys, and two thirds metabolized by the liver.
Maximum plasma levels of rivaroxaban occur 2 4 hours after oral administration and elimination of rivaroxaban from plasma occurs with a terminal half life of 5 9 hours in young individuals, and 11 12 hours in the elderly . Three phase IIb trials, ODIXa HIP2, ODIXa KNEE, and ODIXa OD HIP, were initiated to investigate the antithrombotic potential of rivaroxaban for VTE prevention following major orthopaedic surgery. The primary effi cacy outcome in these trials was the composite of any DVT, non fatal PE, and all cause mortality, and the primary safety outcome was major, post operative bleeding. 1378 Vascular Health and Risk Management 2008:4 Lassen and Laux Table 3 Summary of clinical studies: prevention and treatment of venous thromboembolism Drug Phase Patient population Dosing Comparator Primary endpoint Safety endpoint Results summary VTE prevention Dabigatran etexilate BISTRO II II THR/TKR 50 225 mg bid/ 300 mg od Enoxaparin Incidence of VTE Major bleeding Primary endpoint: 28.5%, 17.4%, 13.1% and 16.6% v