A phase II study of the oral factor Xa inhibitor LY517717 for the prevention of venous thromboembolism after hip or knee replacement

Abstract

To cite this article: Agnelli G, Haas S, Ginsberg JS, Krueger KA, Dmitrienko A, Brandt JT. A phase II study of the oral factor Xa inhibitor LY517717 for the prevention of venous thromboembolism after hip or knee replacement. J Thromb Haemost 2007; 5: 746-53.Summary. Background: LY517717 is an oral direct inhibitor of activated factor X that is currently under clinical development. Objectives: 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. Methods: In a double-blind, parallel-arm, doseranging 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. Results: 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. Conclusions: 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.

Oral, Direct Factor Xa Inhibitors in Development for the Prevention and Treatment of Thromboembolic Diseases

“…The 100, 125, and 150 mg od doses of LY517717 were not inferior to enoxaparin, with similar incidences of the efficacy end point (17.1% to 24.0% versus 22.2% with enoxaparin) and lower incidences of major bleeding (0.0% to 0.9% versus 1.1% with enoxaparin) and minor bleeding (0.0% to 1.0% versus 2.2% with enoxaparin). 62 Dose-response relationships were observed between LY517717 and prolongation of PT, and exposure (measured by the area under the plasma concentration-time curve). Gender and creatinine clearance were found to affect LY517717 exposure and were thus partly responsible for the reported intra-subject variability of 35%.…”

“…Elimination of LY517717 appeared to be primarily via the gastrointestinal route. 62 Based on these findings, a phase II, double-blind, doubledummy, dose-ranging study was initiated to determine the efficacy and safety of LY517717, compared with enoxaparin, for the prevention of VTE in patients undergoing TKR or THR. 62 Patients (Nϭ511) were randomized to receive 1 of 6 oral doses of LY517717 (25,50,75, 100, 125, or 150 mg od) initiated postoperatively, or enoxaparin 40 mg od initiated the evening before surgery.…”

“…62 Based on these findings, a phase II, double-blind, doubledummy, dose-ranging study was initiated to determine the efficacy and safety of LY517717, compared with enoxaparin, for the prevention of VTE in patients undergoing TKR or THR. 62 Patients (Nϭ511) were randomized to receive 1 of 6 oral doses of LY517717 (25,50,75, 100, 125, or 150 mg od) initiated postoperatively, or enoxaparin 40 mg od initiated the evening before surgery. Treatment was continued for a total of 6 to 10 doses; patients underwent mandatory bilateral venography within 12 hours of the last dose and were assessed for symptomatic DVT, PE, and bleeding events until day 30 (Ϯ7) after treatment initiation.…”

Efficacy and safety of novel anticoagulants compared with established agents

“…A phase II study compared six LY517717 (Eli Lilly, Inc.) doses with enoxaparin in acute VTE [Agnelli et al 2005]. The composite endpoint of proximal, distal DVT, and PE ranged from 17.1% to 24% in patients treated with the three highest LY517717 doses.…”

New Antithrombotic Drugs

“…146 LY-517717 was evaluated in a phase 2 noninferiority study that randomized 511 patients undergoing hip or knee arthroplasty to one of six doses of LY-517717 (25, 50, 75, 100, 125, or 150 mg started 6 to 8 h after wound closure) or to once-daily subcutaneous enoxaparin (40 mg started the evening before surgery). 150 Both treatments were administered for a total of 6 to 10 doses. Randomization to the three lower doses of LY-517717 was stopped early due to lack of effi cacy.…”