Warfarin has been used as a thromboprophylactic agent following arthroplasty for over four decades. The vitamin K- dependent factors (II, VII, IX, X) in the coagulation cascade are targeted by warfarin, bringing about a dose-dependent systemic anticoagulation. The use of dose-adjusted warfarin has been validated as an effective strategy in reducing the risk of venous thromboembolism, but its use is associated with a number of challenges. An INR value of at least 2.0 has been advocated by a number of organizations as a target for effective thromboprophylaxis following total hip or knee replacement.5
This requires phlebotomy for anticoagulation monitoring in order to adjust the warfarin dosage to achieve the target INR as a balance between efficacy and safety. Further, significant variation exists in terms of individual response to warfarin, with some patients appearing to be very warfarin-sensitive, while others are relatively warfarin-resistant. Warfarin also has many potential food and drug interactions, so if warfarin use is instituted for prophylaxis against venous thromboembolism, it is critical to obtain a very careful drug inventory from the patient, because potentially serious drug interactions are largely preventable. Absent is a warfarin service to manage anticoagulation, the labor-intensive nature of this strategy serves as a disincentive to the orthopedic surgeon to manage venous thromboembolism prophylaxis by these means.
Low molecular weight heparins have been used since the 1980s and are a class of pharmacologic agents in widespread use for prophylaxis against venous thromboembolism following total hip or knee arthroplasty. Enoxaparin, dalteparin, and nadroparin are representative low molecular weight heparins, and achieve their antithrombotic effect by targeting factor Xa and, to a lesser degree, factor IIa, in the coagulation cascade. Pivotal trials involving the various low molecular weight heparins have generally demonstrated approximately 50% superior efficacy compared with warfarin, with comparable safety.7
Enoxaparin is approved for use as prophylaxis against venous thromboembolism following total hip or knee replacement surgery. Dalteparin has an indication for use following total hip replacement only, and nadroparin is not approved for use in the United States. These agents require subcutaneous injection, so the cooperation of a knowledgeable and compliant patient who is instructed in self-administration, or the use of a family member or nursing personnel, is required in order to employ this strategy successfully. Until recently, no antithrombotic regimen had been found to be superior in efficacy to the North American regimen of enoxaparin 30 mg subcutaneously every 12 hours. Since its introduction into the orthopedic community as a thromboprophylactic agent, it has been anecdotally reported that there is a tendency for patients on enoxaparin to have increased drainage from the surgical site. While efforts to quantify this drainage have been unsuccessful, this is of concern to many orthopedic surgeons because of the potential increase in infection risk. A recently published literature review demonstrates parity in the division between those studies that report an increase in infection in association with hemorrhagic complications following joint arthroplasty with the use of pharmacologic prophylaxis, and those that demonstrate no association.10
Because hospital lengths of stay have gradually declined, an increasingly large proportion of venous thromboembolism events occur post discharge, beyond the realm of surveillance by health care providers. Patient compliance with continued subcutaneous low molecular weight heparin injection post discharge is a concern for many physicians.
Fondaparinux is a selective inhibitor of factor Xa and is also administered once daily by subcutaneous injection. It acts by reversibly binding antithrombin, bringing about a conformational change that leads to irreversible binding with factor Xa. While a meta-analysis of the fondaparinux pivotal trials demonstrates superiority to enoxaparin in reducing the risk of venous thromboembolism following total hip replacement, total knee replacement, and hip fracture,11
this agent has seen less widespread use compared with the low molecular weight heparins. It is currently the only antithrombotic agent with an indication for use in thromboprophylaxis following hip fracture. Like low molecular weight heparins, the need for subcutaneous self-injection is an area of concern with regard to compliance, for both short-term and extended-duration prophylaxis in the post-discharge setting.
Acetylsalicylic acid (aspirin) is not an antithrombotic agent in that it has no effects on the coagulation cascade. It is a nonselective inhibitor of cyclo-oxygenase-1 and cyclo-oxygenase-2. The activity of acetylsalicylic acid leads to inhibition of arachidonic acid conversion to cyclo-oxygenase-2, leading to disruption of platelet aggregation, thereby indirectly reducing the risk of thrombosis.12
While there is ample level 1 scientific evidence to support the efficacy of virtually all antithrombotic agents in decreasing the risk of venous thromboembolism, no level 1 scientific evidence exists for acetylsalicylic acid with regard to venous thrombosis. A significant body of clinical data in support of the efficacy of acetylsalicylic acid in prophylaxis against deep vein thrombosis comes from the arthroplasty series at the University of Pennsylvania,13
where Lotke advocates the use of acetylsalicylic acid 325 mg orally twice daily for 6 weeks as an effective strategy for reducing the risk of deep vein thrombosis.14
Use of acetylsalicylic acid in deep vein thrombosis prophylaxis is employed by approximately 16%–18% of orthopedic surgeons in the United States following total hip or knee replacement. However, many surgeons use low-dose (81 mg) acetylsalicylic acid once daily, although routine use of this dose is not supported in the literature by advocates of acetylsalicylic acid. While acetylsalicylic acid 325 mg orally twice daily is a simple and inexpensive strategy, additional risks posed by this approach center on the risk of upper gastrointestinal bleeding. In the United Kingdom, in an effort to reduce the risk of upper gastrointestinal bleeding, which is increased by up to 3.2-fold with acetylsalicylic acid regimens ranging from 150–300 mg orally twice daily following hip and knee replacement, ranitidine at a dosage of 300 mg once daily has been advocated and is utilized in order to mitigate the hemorrhagic risks associated with acetylsalicylic acid.15
The Pulmonary Embolism Prevention Trial is often cited as supportive evidence of the effectiveness of acetylsalicylic acid in reducing the risk of venous thromboembolism. While this study demonstrated that patients randomized to the acetylsalicylic acid group had fewer venous thromboembolism events compared with placebo in patients following hip fracture, the same was not found in patients following hip and knee replacement.16
Further, patients randomized to the acetylsalicylic acid arm were allowed concurrent use of additional thromboprophylactic measures, including mechanical prophylaxis and even low molecular weight heparin administration, so a study that truly isolates the effects of acetylsalicylic acid is still needed.