Prevention of venous thromboembolism with an oral factor Xa inhibitor, YM150, after total hip arthroplasty. A dose finding study (ONYX-2).

BACKGROUND: Anticoagulant prophylaxis substantially reduces the risk of venous thromboembolism (VTE) after major orthopedic surgery. The direct factor Xa inhibitor YM150 is currently under investigation for the prevention of VTE, stroke and ischemic vascular events in patients after orthopedic surgery, with atrial fibrillation and with acute coronary syndrome, respectively. OBJECTIVES: To investigate the efficacy and safety of YM150 for the prevention of VTE following elective total hip arthroplasty. PATIENTS/METHODS: Patients were randomized to postoperative, once-daily, oral YM150 (5, 10, 30, 60 or 120 mg) (double-blind) or preoperative subcutaneous (open label) enoxaparin (40 mg) for 5 weeks. The primary efficacy endpoint comprised VTE diagnosed by mandatory bilateral venography or verified symptomatic deep vein thrombosis (DVT) plus all deaths up to 9 days after surgery. The primary safety outcome was major bleeding up to 9 days after surgery. RESULTS: Primary efficacy endpoint: of 1017 patients randomized, 960 patients were evaluable for safety and 729 patients for efficacy. A dose-related decrease in VTE incidence from YM150 5 to 60 mg (P = 0.0005) and from 5 to 120 mg (P = 0.0002) was found. The VTE incidence was 27.4%, 31.7%, 19.3%, 13.3% and 14.5% for 5, 10, 30, 60 and 120 mg YM150, respectively, and 18.9% for enoxaparin. Primary safety endpoint: there was one major bleed with YM150 (60 mg) and one with enoxaparin. CONCLUSIONS: The oral direct FXa inhibitor YM150 demonstrated a significant dose response regarding efficacy. Doses from 30 to 120 mg had comparable efficacy to enoxaparin, without compromising safety regarding major bleeding events.

Effects of rosuvastatin and atorvastatin compared over 52 weeks of treatment in patients with hypercholesterolemia.

BACKGROUND: Despite the demonstrated benefits of low-density lipoprotein cholesterol (LDL-C) reduction in reducing the risk of coronary heart disease, many patients receiving lipid-lowering therapy fail to achieve LDL-C goals. We compared the effects of rosuvastatin and atorvastatin in reducing LDL-C and achieving LDL-C goals in patients with primary hypercholesterolemia. METHODS AND RESULTS: In this 52-week, randomized, double-blind, multicenter trial (4522IL/0026), 412 patients with LDL-C 160 to <250 mg/dL received a 5-mg dose of rosuvastatin (n = 138), a 10-mg dose of rosuvastatin (n = 134), or a 10-mg dose of atorvastatin (n = 140) for 12 weeks; during the following 40 weeks, dosages could be sequentially doubled up to 80 mg if National Cholesterol Education Program Adult Treatment Panel II (ATP-II) LDL-C goals were not achieved. At 12 weeks, 5- and 10-mg doses of rosuvastatin were associated with significantly greater LDL-C reductions than 10-mg doses of atorvastatin (46% and 50% vs 39%, both P <.001). At 12 weeks, both rosuvastatin dosages brought more patients to within ATP-II and European LDL-C goals than atorvastatin (86% and 89% vs 73% and 75%, and 86% vs 55%, respectively). At 52 weeks, compared with atorvastatin, both initial rosuvastatin treatment groups significantly reduced LDL-C (47% and 53% vs 44%, P <.05 and P <.001). Overall, more patients in the initial rosuvastatin 10-mg group achieved their ATP-II LDL-C goal than those in the initial atorvastatin 10-mg group (98% vs 87%), with 82% of patients treated with rosuvastatin achieving their goal at the 10-mg starting dosage without the need for titration, compared with 59% of patients treated with atorvastatin. Both treatments were well tolerated over 52 weeks. CONCLUSION: Compared with atorvastatin, rosuvastatin produced greater reductions in LDL-C, which may offer advantages in LDL-C goal attainment over existing lipid-lowering therapies.