Prevention of Venous Thromboembolism in Surgery of the Hip

Aspirin

With the increased awareness on the part of the orthopedic surgeon of the risk of VTE after total hip replacement (THR) surgery and the need for prophylaxis comes a competing awareness of the risk for bleeding with any of the potent anticoagulants. Bleeding in these cases can compromise the results of the surgical procedure. Data from multiple large nonrandomized trials and a systematic review seem to confirm the effectiveness of aspirin (acetylsalicylic acid [ASA]) as a part of a multimodal VTE prophylaxis regimen. Based on these trials, both the American Academy of Orthopaedic Surgeons (AAOS) guidelines and CHEST Guidelines from the American College of Chest Physicians (ACCP) include ASA using their classification as “moderate evidence” in the AAOS guidelines and grade 1B in the Chest Guidelines. No consensus has been established concerning the dosage, with recommendations of 81 mg twice daily, 150 mg once daily or 325 mg once or twice daily. Almost all studies using aspirin indicate a decrease in all-cause mortality, indicating a potential effect on the arterial side, as many all-cause mortality cases were secondary to cardiac deaths. Protocols often use aspirin up to 6 weeks postoperatively, but few are recommending use beyond that time frame. As in all pharmacologic usage, tracking compliance is difficult in the outpatient setting.

Warfarin

Historically, the most common pharmacologic agent of choice for the orthopedic surgeon remained adjusted-dose warfarin sodium, a vitamin K inhibitor with monitoring by an international normalized ratio (INR) both in hospital and into the postoperative rehabilitation period. The drug can be started preoperatively or the first postoperative day; full anticoagulation would not be expected for approximately 3 days. The INR for medical patients is a prolongation on the INR to 2 to 3, but many orthopedic protocols use an INR of 1.5 to 1.9 with other low-dose regimes of an INR of 1.5 to 2.5 to avoid the risk of excessive bleeding ( Table 26.2 ). The half-life of warfarin is 36 to 42 hours, and its effects can be reversed with vitamin K. Because warfarin requires monitoring, compliance of the use of warfarin can easily be tracked. The effectiveness of adjusted-dose warfarin is shown in Table 26.3 . Many factors, including medications, smoking, alcohol, foods, and changes in activity, may interact with warfarin. Because many patients are discharged with warfarin prophylaxis, patients must be made aware of these interactions and must monitor themselves for any symptoms of over-anticoagulation. Optimal use of warfarin requires consideration of the time frame of its effects, use of the INR for close monitoring of effects and interacting factors, patient education, and a systematic approach. As with many of the pharmacologic agents, warfarin is often being used in conjunction with external intermittent compression devices, at least during the hospitalization period.

Low-Molecular-Weight Heparin

The category of drugs most commonly used worldwide for VTE prophylaxis is LMWHs. These drugs are administered subcutaneously and do not require laboratory monitoring or dose adjustment. Extensive data have shown that this category of drugs is safe and effective, although concern still exists about related bleeding. The point at which each of these agents provides inhibition in the coagulation cascade is shown in Fig. 26.1 .

LMWHs were approved for prophylactic use for THA in 1993 and have been adopted in practice by many clinicians. The LMWHs most commonly used in North America are enoxaparin and dalteparin (see Table 26.2 ). LMWHs have been studied extensively and are highly effective and generally safe. Pooled results from clinical trials are shown in Table 26.3 .

LMWHs are pharmacologically different from unfractionated heparin. LMWHs bind less to proteins and endothelial cells, resulting in a more predictable dose response, a dose-independent mechanism of clearance, and a longer plasma half-life.

With highly predictable pharmacokinetic properties and high bioavailability, LMWHs have the ability to target factor Xa while affecting factor IIa to a lesser extent (see Fig. 26.1 ) and are associated with a lower incidence of thrombocytopenia than unfractionated heparin. The half-life of LMWH is 4.5 hours, and its effects can be reversed by protamine sulfate. Its propitious pharmacokinetics allows LMWH administration subcutaneously once or twice daily without requisite monitoring of drug levels or activity.

The possibility of increased bleeding remains a concern with LMWH prophylaxis ( Table 26.4 ).

Factor Xa Inhibitors

Fondaparinux, a synthetic pentasaccharide given subcutaneously that anticoagulates through inhibition of factor Xa (see Fig. 26.1 ), has been shown to provide effective prophylaxis in a once-daily dose in THA and hip fracture surgery (see Table 26.2 ). This pentasaccharide has a half-life of 18 hours with no known antidote. The reported total incidence of DVT in THA is shown in Table 26.3 . The bleeding rate is reported in Table 26.4 .

Rivaroxaban is an orally administered selective direct inhibitor of factor Xa with a half-life of approximately 9 hours and a rapid onset of action, reaching maximum serum concentration in less than 2 hours (see Table 26.2 ). Rivaroxaban has been reported in two clinical trials after THA, both comparing rivaroxaban with enoxaparin. One trial with treatment for 35 days reported a VTE rate of 1.1% (18/1595) with rivaroxaban and 3.7% (58/1558) with enoxaparin. The other trial, with 31 to 39 days of treatment with rivaroxaban and 10 to 14 days of enoxaparin treatment, reported a VTE rate of 2.0% (17/864) and 9.3% (81/869), respectively. Bleeding was reported to be similar with the two treatments in both studies.

Apixaban, also orally administered, is a selective factor Xa inhibitor with a half-life of approximately 12 hours and reaches maximum concentration within 3 to 4 hours. This drug is given in twice-daily doses for a period of 35 days ( Table 26.2 ). Apixaban clinical trials for prophylaxis in THA using the drug for 10 to 14 days compared with enoxaparin reported a VTE rate of 0.5% (10/2199) for apixaban and 1.1% (25/2195) for enoxaparin, with similar bleeding events.