Thrombosis Express Report

Publication date: 2005-12-31

Advancements in the Management of Venous Thromboembolic Disorders

Expert Commentary

Provided by John G. Kelton, MD, Professor, Department of Medicine, and The Department of Pathology & Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada

Venous thromboembolism, whether manifested as deep vein thrombosis or pulmonary embolism, is a common risk for patients undergoing abdominal, cancer, orthopedic and other major surgeries. With over 200,000 new cases diagnosed annually,¹ venous thrombo-embolism is a cause of significant morbidity and mortality. For example, without anticoagulant prophylaxis, the incidence of deep vein thrombosis in patients undergoing total hip or knee arthroplasty can be as high as 50% to 60% by 2 weeks following surgery. ² Depending on the surgical procedure, the incidence of fatal pulmonary embolism in patients receiving no anticoagulant prophylaxis has been reported as high as 7.0%.^3,4

Conventional treatment options for the prophylaxis and treatment of venous thromboembolism include unfractionated heparin, low-molecular-weight heparins and vitamin K antagonists (eg, warfarin), among other interventions. Until recently, unfractionated heparin was the most widely used agent for the prophylaxis and treatment of venous thromboembolism. However, unfractionated heparin carries several disadvantages that include a variable plasma half-life which can result in a marked variability in anticoagulant response. ⁵ In addition, unfractionated heparin is generally administered by continuous intravenous administration with dosing adjustments determined through laboratory monitoring of coagulation tests. Heparin, especially unfractionated heparin, also carries a significant risk of heparin-induced thrombocytopenia (HIT). Outcomes associated with the development of HIT can include venous or arterial thrombosis, amputation, and death. ⁶ Approximately 50% of patients with HIT develop a thromboembolic event, ⁷ of which approximately 20% will require amputation and 30% will die. ⁸

Low-molecular-weight heparins (enoxaparin, dalteparin, tinzaparin) have a more consistent and reproducible half-life following once- or twice-daily subcutaneous administration, when compared to unfractionated heparin. Additionally, they have longer plasma half-lives, improved bioavailability, and a more predictable anticoagulant response. ⁵ Low-molecular-weight heparins have also been associated with the development of HIT, ^9,10 although at a significantly lower risk than unfractionated heparin. Effective treatment of HIT includes immediate withdrawal of all heparins and initiation of a direct thrombin inhibitor (eg, argatroban or lepirudin). ¹¹

Significant progress has been made in the treatment and prophylaxis of venous thromboembolic disorders over the last several years. Newer anticoagulant agents offer potential advantages over tra-ditional anticoagulant therapies with improved pharmacologic and clinical profiles. ¹² One of the first of these agents, fondaparinux, has been studied extensively in clinical trials over the past several years. Fondaparinux is the first in a new class of synthetic pentasaccharide anticoagulants that binds selectively to antithrombin and directly inhibits the action of factor Xa. ¹³ Fondaparinux has been evaluated for the treatment of venous thromboembolism in a number of large clinical trials. ^14-16 Results have demonstrated fondaparinux was at least comparable to unfractionated heparin for the initial treatment of pulmonary embolism and to low-molecular-weight heparin for the initial treatment of deep vein thrombosis. ^14,15 The pharmaco-kinetic profile of fondaparinux is characterized by a high bioavailability following subcutaneous administration, slow elimination (allowing once-daily administration), and dose-dependent clearance. ¹⁷ The predictable anticoagulant response of fondaparinux obviates the need for laboratory monitoring. Addi