Prevention of venous thromboembolism in the orthopedic surgery patient

PHARMACOLOGIC OPTIONS FOR VTE PROPHYLAXIS IN ORTHOPEDIC SURGERY

As reviewed in the introductory article of this supplement, the arsenal of anticoagulants for use in VTE prophylaxis includes low-dose unfractionated heparin (UFH), low-molecular-weight heparin (LMWH) agents such as dalteparin and enoxaparin, and the factor Xa inhibitor fondaparinux. A few additional comments about these and other anticoagulant options is warranted in the specific context of orthopedic surgery.

Fondaparinux. Because most of its formal US indications are for use as VTE prophylaxis in major orthopedic surgery—including hip replacement, knee replacement, and hip fracture repair—fondaparinux has been studied more widely in orthopedic surgery patients than in the other populations reviewed earlier in this supplement. Nevertheless, its use even in these settings has remained somewhat limited. This may be because of concerns over possible increased bleeding risk relative to some other anticoagulants. Because of bleeding risk, fondaparinux is contraindicated in patients who weigh less than 50 kg, and its package insert recommends caution when it is used in the elderly due to an increased risk of bleeding in patients aged 65 or older. Additionally, the Pentasaccharide in Major Knee Surgery (PENTAMAKS) study found fondaparinux to be associated with a significantly higher incidence of major bleeding compared with enoxaparin (2.1% vs 0.2%; P = .006) in major knee surgery, although it was superior to enoxaparin in preventing VTE.¹⁰ Other possible reasons for slow adoption of fondaparinux include its long half-life, which results in a sustained antithrombotic effect, its lack of easy reversibility, and a contraindication in patients with renal insufficiency.¹¹

Limited role for UFH. Low-dose UFH has a more limited role in orthopedic surgery than in other settings requiring VTE prophylaxis, as current ACCP guidelines for VTE prevention recognize it only as a possible option in hip fracture surgery and state that it is not to be considered as sole prophylaxis in patients undergoing hip or knee replacement.⁶

Warfarin. Although not indicated for use in other VTE prophylaxis settings, the vitamin K antagonist warfarin is recommended as an option for all three major orthopedic surgery indications—knee replacement, hip replacement, and hip fracture repair.⁶

The key to effective prophylaxis with warfarin is achieving the appropriate intensity of anticoagulation. In two separate analyses, Hylek et al demonstrated a balance between safety and efficacy with warfarin therapy targeted to an international normalized ratio (INR) of 2.0 to 3.0.^12,13 An INR greater than 4.0 greatly increased the risk of intracranial hemorrhage, whereas thrombosis was not effectively prevented with an INR less than 2.0.^12,13 This latter point should be stressed to orthopedic surgeons, who sometimes aim for INR values below 2.0.

Although anticoagulation clinics are superior to usual care at maintaining the INR within the window of 2.0 to 3.0, only about one-third of patients nationally who take warfarin receive care in such clinics.¹⁴ Even with optimal care in anticoagulation clinics, some patients will still receive subtherapeutic or supertherapeutic levels of warfarin, which is one of this agent’s limitations.

Aspirin not recommended as sole agent. Although aspirin is still used as thromboprophylaxis in orthopedic surgery patients, current ACCP guidelines recommend against its use as the sole means of VTE prophylaxis in any patient group.⁶ The limitations of the evidence for aspirin in this setting are illustrated by the Pulmonary Embolism Prevention study, a multicenter randomized trial in patients undergoing hip fracture (n = 13,356) or hip/knee replacement (n = 4,088).¹⁵ Patients received aspirin 160 mg/day or placebo for 5 weeks, starting preoperatively, and were evaluated for outcomes at day 35. Among the hip fracture patients, the rate of symptomatic DVT was lower in the aspirin group than in the placebo group (1.0% vs 1.5%; P = .03), as was the rate of PE (0.7% vs 1.2%, respectively; P = .002), but there was no significant difference in outcomes between the groups among the patients undergoing hip or knee replacement. Notably, 40% of patients in the study also received UFH or LMWH. Further confounding the results, some patients received nonpharmacologic VTE prophylaxis modalities, and others received nonsteroidal anti-inflammatory drugs other than aspirin.

Heparin-induced thrombocytopenia. As noted earlier in this supplement, the incidence of heparin-induced thrombocytopenia (HIT) is markedly higher in patients who receive UFH than in those who receive LMWH. This difference in frequency, which constitutes about a sixfold to eightfold differential, is due to the relationship between standard heparin and platelet factor IV, which can induce formation of IgG antibodies.¹⁶ A 50% or greater reduction in platelet count in heparin recipients should prompt consideration of HIT.

Oral direct thrombin inhibitors. Although the oral direct thrombin inhibitor ximelagatran was rejected for approval by the US Food and Drug Administration (FDA) and recently withdrawn from the market world­wide as a result of hepatic risks, other oral direct thrombin inhibitors are in phase 3 studies for use in orthopedic surgery and may be commercially available options for postoperative VTE prophylaxis before long.

GUIDELINES FOR VTE PROPHYLAXIS IN ORTHOPEDIC SURGERY

The ACCP guidelines referred to throughout this article are widely recognized as a practice standard for VTE prevention and treatment, and have been regularly updated throughout recent decades. The most recent version, issued in 2004, is formally known as the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.⁶ Key orthopedic surgery-related recommendations and notable changes from the previous version of the guidelines, issued in 2001, are outlined below, along with pertinent supportive or illustrative studies.

Hip replacement surgery

In a change from the previous guidelines, the Seventh ACCP Conference recommends extended prophylaxis, for up to 28 to 35 days after surgery, for patients undergoing hip replacement or hip fracture surgery. For hip replacement surgery, this is a Grade 1A recommendation for prophylaxis with either LMWH or warfarin and a Grade 1C+ recommendation (“no RCTs but strong RCT results can be unequivocally extrapolated, or overwhelming evidence from observational studies”) for prophylaxis with fondaparinux.⁶

Reprinted, with permission, from Annals of Internal Medicine (Hull et al, 2001).17