ly517717 and Thromboembolism

Anticoagulants are recommended for the prevention and treatment of a wide variety of thromboembolic events. Although existing anticoagulants are effective, their use is limited by parenteral administration or the requirement for frequent monitoring and subsequent dose adjustment. Therefore, there is an urgent need for novel, oral agents with a predictable anticoagulant action. Because of its key position in the coagulation cascade and its limited roles outside of coagulation, Factor Xa has emerged as an attractive target for novel anticoagulants. As a result, the past decade has witnessed an explosion of research into small-molecule, oral, direct Factor Xa inhibitors, and several are now in clinical development. Rivaroxaban, LY517717, YM150, apixaban, PRT054021, and DU-176b, among others, have shown considerable promise; rivaroxaban is currently furthest ahead in its developmental program, having entered phase III in 3 indications. It is hoped that, before long, these anticoagulants will allow us to enter an era of convenient, oral anticoagulation, without the need for regular monitoring or dose adjustment.

Topics: Administration, Oral; Animals; Anticoagulants; Blood Coagulation; Drugs, Investigational; Factor Xa; Factor Xa Inhibitors; Glycine; Humans; Morpholines; Piperazines; Rivaroxaban; Thiophenes; Thromboembolism; Treatment Outcome

LY517717 is an oral direct inhibitor of activated factor X that is currently under clinical development.. The aims of this proof-of-concept study in patients undergoing total knee replacement (TKR) or total hip replacement (THR) were to determine whether LY517717 can safely reduce the risk of venous thromboembolism (VTE) and to identify at least one dose of LY517717 that is non-inferior to enoxaparin.. In a double-blind, parallel-arm, dose-ranging study, patients undergoing TKR or THR were randomly allocated to receive once-daily oral LY517717 (25, 50, 75, 100, 125 or 150 mg), started 6-8 h after wound closure, or s.c. enoxaparin, 40 mg, started in the evening before surgery. The primary efficacy endpoint was the composite of deep venous thrombosis (DVT), detected by mandatory bilateral venography performed at the end of the study treatment (between days 5 and 9), and objectively confirmed symptomatic DVT and/or pulmonary embolism (PE), occurring during the treatment period. The combination of major and minor bleeding was the primary safety endpoint.. Five hundred and seven patients received at least one dose of LY517717 or enoxaparin (safety population). Three hundred and ninety-one patients had evaluable bilateral venography or experienced a clinical DVT and/or PE (primary efficacy population). LY517717 treatment resulted in a dose-dependent decrease in the incidence of thromboembolic events (P = 0.0001). The incidences of VTE with 100, 125, and 150 mg of LY517717 were 19%, 19% and 16%, respectively, compared to 21% with enoxaparin. The efficacies of 100-mg, 125-mg and 150-mg doses of LY517717 were non-inferior to that of enoxaparin according to prespecified criteria. Bleeding events were uncommon in both LY517717 and enoxaparin patients.. Doses of 100, 125 and 150 mg of LY517717 are non-inferior to enoxaparin for the prevention of VTE after TKR or THR, and are associated with similar low rates of bleeding.

Topics: Adult; Aged; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Female; Glycine; Humans; Male; Middle Aged; Piperazines; Postoperative Complications; Thromboembolism; Treatment Outcome; Venous Thrombosis

Topics: Anticoagulants; Clinical Trials as Topic; Factor Xa Inhibitors; Fondaparinux; Glycine; Humans; Morpholines; Piperazines; Polysaccharides; Rivaroxaban; Thiophenes; Thromboembolism