ATLANTA, Dec. 11 /PRNewswire/ -- Blood clotting -- a natural, protective mechanism that is triggered by the body in response to a cut or wound -- is essential to prevent excessive bleeding. When blood clotting malfunctions, a clot (or thrombus) forms inside a blood vessel, obstructing the flow of blood through the circulatory system. Two studies that highlight new ways to prevent and treat blood clotting complications after major surgery will be presented today at the 47th Annual Meeting of the American Society of Hematology.
Deep vein thrombosis (DVT), a common condition that is difficult to detect in many patients, is the formation of a blood clot which may partially or completely block a blood vessel. These clots form in one of the large, deep veins of the body, usually in the calf, thigh, knee, or pelvis. Patients with untreated clots can develop a pulmonary embolism (PE), causing severe respiratory dysfunction. PE is the most serious complication of DVT and occurs when a blood clot in the vein breaks up into smaller pieces and travels to other parts of the body. Major operations, particularly those involving the lower half of the body, increase a patient’s risk of developing DVT or PE.
“Since we are aware of the risk factors, thromboembolic disorders should be preventable or easily treated,” said Katherine A. High, M.D., Howard Hughes Medical Institute, Philadelphia, Penn. “Current therapies, though effective, still have many limitations and undesirable side effects. Technological advances in this area and new treatment options with increased safety and efficacy are greatly needed.”
Thromboprophylaxis After Orthopedic Surgery With an Oral, Direct Factor Xa Inhibitor: Pooled Results of Two Phase llb Clinical Trials [Abstract 277]
Thromboembolic events, such as DVT and PE, are a serious risk after surgical procedures such as major orthopedic surgery. BAY 59-7939 (BAY) is an oral, direct Factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. Factor Xa is the common point between extrinsic pathways (which initiate the clotting process) and intrinsic pathways (which amplify the clotting process). BAY only inhibits Factor Xa and does not require the presence of any other substances -- commonly called co-factors -- to exert its effects.
This particular study joins data from two previous multi-center, multi-national, double-blind, dose-ranging studies in which the efficacy and safety of BAY for thromboprophylaxis was determined relative to enoxaparin. The first trial was conducted in Europe, studying patients who underwent elective total hip replacement surgery (THR), and the second trial was conducted in North America, looking at patients who underwent elective total knee replacement surgery (TKR).
A total of 1,343 patients were randomized to receive either twice daily (BID) doses of oral BAY ranging from 2.5 to 30 mg, or subcutaneous enoxaparin (40 mg once daily starting 12 hours before hip surgery or 30 mg BID starting 12 hours after knee surgery). Treatment continued until mandatory bilateral venography -- an X-ray study of veins on both the right and left sides of the body using dye to outline veins and identify problems -- was performed five to nine days after surgery. The primary efficacy endpoint was a composite of DVT, PE, and all-cause mortality, and the secondary efficacy endpoint was major venous thromboembolism (VTE). The primary safety endpoint was major, postoperative bleeding, and was analyzed in 1,317 patients.
No significant dose-response relationship for efficacy was observed with BAY. This was potentially due to the effectiveness achieved with the lower BAY doses. However, a significant dose-response relationship was observed for major, postoperative bleeding with BAY (P<0.001).
“The analysis of these phase II data confirms that a total daily dose of 5 to 20 mg of oral BAY has similar efficacy and safety to subcutaneous enoxaparin for the prevention of thromboembolic events after major orthopedic surgery. It is important to note that no dose arm was discontinued because of safety concerns in these studies or a lack of efficacy,” said Alexander G.G. Turpie, M.D., Hamilton Health Sciences-General Hospital, Hamilton, Ontario, Canada. “Moreover, the safety and efficacy of this dose range of BAY in this setting has been confirmed in other similar studies.”
A Phase II Study of the Safety and Efficacy of a Novel Oral fXa Inhibitor (LY517717) for the Prevention of Venous Thromboembolism Following TKR or THR [Abstract 278]
Although considerable progress has been made in the treatment of VTE, new advancements are emerging that have the potential to rapidly change the therapeutic scenario. LY517717, an investigational oral direct inhibitor of activated Factor Xa, appears to interrupt thrombus formation without impairing platelet hemostatic function.
This double-blind, double-dummy, dose-escalation study was conducted to investigate the safety and efficacy of LY517717 and how one or more doses compare to enoxaparin in preventing VTE in patients undergoing TKR or THR. In the study, 511 patients undergoing TKR or THR were randomized to receive one of six oral doses of LY517717 (25, 50, 75, 100, 125, or 150 mg) once daily or a daily dose of 40 mg enoxaparin. Both treatments were continued for a total of six to 10 doses. Three hundred and ninety-one patients had an evaluable bilateral venogram or experienced an objectively confirmed clinical VTE and were included in the efficacy analyses. The three lowest doses were stopped early due to lack of efficacy, and the study was completed with the three highest doses.
Patients underwent mandatory bilateral venography within 12 hours of the last dose of the oral study drug and were assessed for symptomatic DVT, PE, and bleeding events through day 30 (+/- 7). Symptomatic DVT and PE events were included in the combined VTE endpoint. The 100, 125, and 150 mg doses of LY517717 were non-inferior to enoxaparin in the incidence of symptomatic or venographic DVT or PE. Bleeding events were uncommon in both LY517717 and enoxaparin patients.
“LY517717 has been well tolerated in healthy subjects and is being developed in hopes of addressing the need for therapies to prevent VTE,” said Giancarlo Agnelli, M.D., University of Perugia, Perugia, Italy. “The results of this study suggest that 100, 125, and 150 mg doses of this drug may have similar effects as 40 mg of enoxaparin for the prevention of VTE following total knee or hip replacement surgery, with no significant difference in bleeding risk when compared with enoxaparin. This opens a large scenario for this agent, including the possible use in atrial fibrillation and the treatment of VTE. In these indications the availability of an oral agent would be of remarkable importance.”
The American Society of Hematology (www.hematology.org) is the world’s largest professional society concerned with the causes and treatment of blood disorders. Its mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems, by promoting research, clinical care, education, training, and advocacy in hematology.
The American Society of Hematology
CONTACT: Leslie Priest, Spectrum Science Communications, +1-202-955-6222,lpriest@spectrumscience.com; Aislinn Raedy, American Society of Hematology,+1-202-776-0544, araedy@hematology.org, or On-site (12/9-12/13),+1-404-222-5705
Web site: http://www.hematology.org/