Prevention of VTE After Orthopedic Surgery

The clinical utility of fondaparinux as a method of thromboprophylaxis following orthopedic surgery was established by four, large phase III studies in which patients were randomized to receive either fondaparinux or enoxaparin. Two studies (EPHESUS, PENTATHLON 2000) were performed in patients undergoing elective hip replacement (Lassen et al., 2002; Turpie et al., 2002b). With a primary outcome measure of venographically evident deep-vein thrombosis (DVT) and symptomatic VTE, fondaparinux demonstrated superior efficacy compared to once-daily dosing of enoxaparin (40 mg; EPHESUS) and comparable efficacy to twice-daily dosing (30 mg b.i.d.; PENTATHLON 2000). Major bleeding was not statistically different between the two groups. In a study of patients undergoing elective knee replacement surgery (PENTAMAKS), fondaparinux demonstrated superior efficacy (defined above) compared to enoxaparin (Bauer et al., 2001).

A fourth registration study (PENTHIFRA) enrolled patients undergoing hip fracture surgery (Eriksson et al., 2001). Here, fondaparinux demonstrated a marked reduction in postoperative DVT and VTE compared to enoxaparin (8.3% vs. 19.1%; p < 0.001). Bleeding was not significantly different between the two treatment groups. To investigate the utility of extended prophylaxis following hip fracture surgery, a fifth orthopedic trial was undertaken (PENTHIFRA-Plus) (Eriksson and Lassen, 2003). Patients completing a standard course of therapy with 2.5 mg of fondaparinux given for 6-8 days were randomized to additional therapy versus placebo for 19-23 days. The primary efficacy outcome, symptomatic or venographically evident VTE, was markedly reduced by extended therapy (1.4% vs. 35%; p < 0.001). Fondaparinux received approval from the U.S. Food and Drug Administration (FDA) for the prevention of VTE following major hip or knee surgery (Table 2).

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