Selective Factor Xa Inhibition Improves Efficacy of Venous Thromboembolism Prophylaxis in Orthopedic Surgery

Philip C. Comp, M.D., Ph.D.


Pharmacotherapy. 2003;23(6) 

In This Article

Abstract and Introduction

Venous thromboembolism is a serious, frequent, and potentially fatal complication of major orthopedic surgery. Currently available pharmacologic agents for the prevention of venous thromboembolism in this high-risk population consist of the oral anticoagulants and the heparin family of antithrombotic agents (unfractionated heparin, low-molecular-weight heparin, heparinoids). These classes of agents interfere with the activity of both thrombin and factor Xa (or their respective zymogens) to varying degrees. Newer antithrombotic agents in various stages of development exert their antithrombotic effect through a more targeted mechanism of action. Direct factor Xa inhibitors and the newest class of antithrombotic agents, the indirect factor Xa inhibitors, the prototype of which is the synthetic pentasaccharide fondaparinux sodium, limit fibrin formation through their exclusive inactivation of factor Xa. Clinical data from venous thrombo-embolism prophylaxis trials in hip and knee replacement and hip fracture surgeries, including the recently completed fondaparinux phase II and phase III trials, indicate that selective antifactor Xa activity may improve the efficacy:safety ratio of antithrombotic therapies for the prevention of venous thromboembolism in high-risk major orthopedic surgery.

Major orthopedic surgery of the hip and knee is associated with a high risk of venous thromboembolism, including deep vein thrombosis (DVT) and its potentially fatal complication, pulmonary embolism. According to pooled clinical trial data summarized in the most recent guidelines for prevention of venous thromboembolism issued by the American College of Chest Physicians (ACCP),[1] in the absence of prophylaxis the prevalence rates of DVT in patients undergoing total hip replacement, total knee replacement, and hip fracture surgeries are 64%, 54%, and 48%, respectively. Proximal DVT (blood clots that occur in veins at the level of the knee or in the upper leg), which is the source of pulmonary emboli, accounts for a significant proportion of DVT events in these patients, with prevalence rates of 25% reported for the two hip surgery populations and 15% for the total knee replacement population.[1] Among these three surgical groups, hip fracture repair carries the highest risk of fatal pulmonary embolism (4-12% vs < 1% for the others), whereas hip and knee replacement are associated with an increased risk of nonfatal pulmonary embolism (based on total prevalence rates [i.e., fatal plus nonfatal] of 1-30% and 2-7%, respectively).[1]

In an effort to reduce the morbidity and mortality associated with the complications of venous thromboembolism after major orthopedic surgery, antithrombotic therapy has become an integral part of the medical treatment of this high-risk population. The earliest pharmacologic agents introduced for venous thromboembolism prophylaxis, the oral vitamin K antagonists (e.g., warfarin), continue to be administered today for the prevention of DVT in patients undergoing orthopedic surgery. Pharmacologic interventions based on natural anticoagulant mechanisms (i.e., the heparin family of antithrombotic agents) have gained equal prominence over the past several decades. These agents include unfractionated heparin, low-molecular-weight heparin (LMWH), and the heparinoids. The most recent ACCP guidelines for venous thromboembolism prophylaxis in major orthopedic surgery recommend heparin family-based regimens as an appropriate alternative to warfarin.[1]

Despite improvements in risk reduction with the available antithrombotic agents (compared with no treatment), the residual prevalence of venous thromboembolism complications after major orthopedic surgery remains unacceptably high. Even with the "best" agent in a given indication, adequate reduction in DVT incidence either is not achieved or comes at the expense of safety (i.e., results in excessive bleeding or other medical complications).

The past 2 decades have witnessed intense activity in the development of new, selective antithrombotic therapies. In large part, the development of these agents takes into account the advantages of limiting fibrin formation by selectively inhibiting individual components of the coagulation cascade. This approach may overcome the biologic and pharmacologic limitations of current agents, thus offering improved efficacy and safety in venous thromboembolism prophylaxis. Included among these newer classes of antithrombotic agents are direct thrombin inhibitors,[2] direct factor Xa (activated factor X) inhibitors,[3] and indirect factor Xa inhibitors.[4]


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