Background Patients undergoing orthopedic surgery are at particularly high risk for venous thromboembolism (VTE) and as such often receive prophylactic low-molecular-weight heparin (LMWH) or warfarin. However, efficacy and safety limitations of these agents have prompted a search for alternative antithrombotic drugs. Methods A new pentasaccharide, Org31540/SR90107A, the first of a class of synthetic and highly selective Factor Xa inhibitors, was investigated in a phase II double-blind, dose-ranging study for the prevention of deep vein thrombosis in 933 patients undergoing elective total hip replacement. The assessor-blind, comparative control was the LMWH enoxaparin. Patients were randomly assigned to 1 of 5 Org31540/SR90107A treatment groups (0.75, 1.5, 3, 6, or 8 mg/d subcutaneously) or to 30 mg enoxaparin subcutaneously every 12 hours. Treatment was started after surgery and continued for 5 to 10 days. Principal outcomes, determined on the basis of standard criteria, included venographically detected deep vein thrombosis and major bleeding. The 6.0- and 8.0-mg groups were discontinued early, in accordance with a protocol-defined safety rule. Results This phase II study showed improved dose-related efficacy and safety for Org31540/SR90107A versus enoxaparin and led to selection of 2.5 mg once daily as the optimal Org31540/SR90107A dose for large phase III trials in the prevention of VTE after total hip replacement, total knee replacement, and surgery for fractured hip. These studies have now been completed. Conclusions Org31540/SR90107A is a new synthetic antithrombotic agent that has demonstrated a significant efficacy and safety dose effect in VTE prophylaxis after orthopedic surgery. (Am Heart J 2001;142:S9-15.)