Chapter 137 Prevention of Venous Thromboembolism in Knee Surgery

Limitations of Aspirin and Mechanical Devices

Combined Mechanical and Pharmacologic Prophylaxis

NEURAXIAL (EPIDURAL AND SPINAL) ANESTHESIA

It is estimated that venous thromboembolism (VTE) accounts for up to 160 cases of deep vein thrombosis (DVT), 20 cases of symptomatic nonfatal pulmonary embolism (PE), and 50 cases of fatal PE/100,000/year.²⁴ Deaths from VTE are greater in number than deaths from bowel cancer, prostate cancer, breast cancer, road traffic accidents, or HIV/AIDS.² PE is the most common preventable cause of hospital death.¹⁰ An often overlooked long-term consequence of DVT is the post-thrombotic syndrome, leading to chronic venous insufficiency (CVI) and chronic venous leg ulceration; the incidence is approximately 300 cases/100,000, with approximately 25% being caused by previous DVT that may have been asymptomatic and undiagnosed. Another well-documented debilitating long-term consequence of VTE is chronic thromboembolic pulmonary hypertension.^14,²⁶

The risk of VTE increases substantially with age ¹⁰ and DVT occurs in approximately 50% of patients undergoing certain types of surgery if prophylaxis is not used (Table 137-1). Patients undergoing total knee arthroplasty (TKA) without VTE prophylaxis have been shown to have a mean DVT incidence of 47% (95% confidence interval [CI], 42% to 51%), placing them in the highest risk category for postoperative VTE.

Table 137-1 Frequency of Deep Vein Thrombosis in Surgery Patients Without Prophylaxis

In randomized controlled trials to demonstrate the effectiveness of pharmacologic agents for VTE prophylaxis, objective measures are required for the assessment of VTE. The use of mandatory venography has been widely adopted as a surrogate outcome measure to assess the efficacy of anticoagulant drugs. There is skepticism among some clinicians as to whether asymptomatic DVT detected by venography is clinically relevant.⁵ However, there is a strong correlation between asymptomatic DVT and symptomatic VTE.²⁷ Furthermore, it is important to prevent asymptomatic events to avoid the development of potentially more serious secondary events.

Although there is extensive evidence to guide appropriate VTE prophylaxis, surveys have shown that the evidence is not always followed in daily clinical practice. For effective VTE prophylaxis of surgical patients, it is important to assess the individual patient’s VTE risk in relation to the underlying clinical condition and to balance this against the bleeding risk in choosing the most appropriate prophylaxis for that patient. The assessment for VTE prophylaxis should occur on admission to hospital and prophylaxis should commence without undue delay and be reassessed on a regular basis to ensure that it remains appropriate. In patients with a prolonged hospital stay prior to surgery, prophylaxis should be initiated during the preoperative period. Continued encouragement of ambulation and adequate hydration are important principles for all patients, regardless of their risk category.

Methods of Prophylaxis

Mechanical Prophylaxis

Graduated Compression Stockings

There is some evidence that graduated compression stockings (GCS) can reduce the incidence of DVT.³ There are fewer studies of GCS compared with those of pharmacologic prophylaxis and these have mostly involved full-length stockings. Although it is anticipated that below-knee stockings should provide a degree of protection against DVT, there are few comparative studies. There are two types of GCS, one for DVT prophylaxis and the other for treatment of CVI. The following are general recommendations for the use of GCS for VTE prophylaxis: (1) they should be worn continuously during the period of immobility to the return of full ambulation; (2) they are contraindicated in patients with critical limb ischemia; (3) they should be measured and fitted for the individual patient; and (4) patient compliance is essential (e.g., ensuring that stockings are not “rolled down”. There is a wide range of available GCS and the choice should take into account their clinical efficacy in providing a pressure of 16 to 20 mm Hg at the ankle, with the patient in a supine position, with graduated compression to the knee or above. Washing and reuse guidelines should be provided and GCS should conform to appropriate manufacturing standards, with independent testing on their compression profile using internationally accepted methods.

Intermittent Pneumatic Compression

Intermittent pneumatic compression (IPC) has also been shown to reduce the incidence of DVT.³ It is more effective than GCS in high-risk patients in combination with anticoagulants or when anticoagulants are contraindicated.

Foot Impulse Technology and Venous Foot Pump

Foot impulse technology (FIT) and a venous foot pump (VFP) are devices that can be used with GCS if it is not possible to use IPC. The recommended use of IPC and VFP devices for DVT prophylaxis is similar to that for GCS in that they should be used from the time of immobility to the return of full ambulation and not used in limbs with critical ischemia.

Pharmacologic Prophylaxis

Over the past 30 years, there have been a large number of randomized controlled trials providing indisputable evidence that pharmacologic prophylaxis reduces the risk of VTE. In some early placebo-controlled studies, a reduction in the incidence of fatal PE was noted.¹⁰ In subsequent trials, in which one drug was compared with another without a placebo-controlled group, it has been difficult to demonstrate a statistically significant difference in the end point of fatal PE, because its incidence is already low in the comparator drug group being compared with the study drug group. In addition, if an asymptomatic DVT is detected, it will be treated, which will influence the natural history and incidence of PE.

Acetylsalicylic Acid

Acetylsalicylic acid (ASA) has been advocated for VTE prophylaxis after major orthopedic surgery.¹³ However, compared with other available pharmacologic prophylactic agents, it is relatively ineffective. One meta-analysis has shown a benefit for ASA with a reduction in DVT and PE compared with controls, but the reduction was far less than that seen with anticoagulant drugs; other studies have shown no significant benefit with ASA for VTE prophylaxis or have shown that ASA is inferior to other pharmacologic prophylactic agents.¹⁰

New Oral Anticoagulants

Recent studies have shown that newer oral anticoagulants may be as effective, or even more effective, than current pharmacologic agents, which are in standard use for VTE prophylaxis.⁷^–⁹ ^,15 ^,20 ^,31

Dabigatran Etexilate

Dabigatran is an oral direct thrombin inhibitor. Two phase III studies have evaluated dabigatran for the prevention of VTE after TKA. The RE-MOBILIZE ¹¹ study randomized 2615 patients to receive dabigatran, 150 mg once daily, dabigatran, 220 mg once daily, or the North American regimen of enoxaparin, 30 mg twice daily for 12 to 15 days. The primary efficacy outcome for dabigatran, 150 and 220 mg, and enoxaparin occurred in 33.7%, 31.1%, and 25.3% of patients, respectively, with dabigatran failing to meet the noninferiority criteria for the primary efficacy outcome compared with enoxaparin. There were numerically less major bleeding events—0.6% for dabigatran compared with 1.4% for enoxaparin—but this was not statistically significant. In the RE-MODEL⁹ study, the European enoxaparin dosage of 40 mg, once daily for 6 to 10 days, was used and dabigatran was shown to be noninferior compared with enoxaparin. The incidence of major bleeding was similar between the groups.

Rivaroxaban

Rivaroxaban is an oral direct factor Xa inhibitor. There have been four randomized, double-blind, phase III studies (RECORD1, 2, 3, and 4) investigating rivaroxaban for the prevention of VTE in patients undergoing total hip arthroplasty (THA) or TKA.²¹ A total of 12,729 patients were randomized to receive oral rivaroxaban, 10 mg once daily, starting 6 to 8 hours after surgery or subcutaneous enoxaparin, 40 mg once daily, starting the evening before surgery (RECORD1–3) or 30 mg twice daily, starting 12 to 24 hours after wound closure (RECORD4). RECORD3 recruited patients undergoing TKA for whom the European regimen of enoxaparin was used, whereas patients in RECORD4 received the North American regimen of enoxaparin following TKA. In both RECORD3 and RECORD4, prophylaxis was continued for 10 to 14 days. All patients were followed up for 30 to 35 days after the last dose of study medication.

The primary efficacy outcome measure of any DVT, nonfatal PE, and all-cause mortality was the same in all four studies. The rivaroxaban regimens significantly reduced the incidence of the primary efficacy outcome in each of the studies compared with the enoxaparin regimens, with similar rates of major bleeding in both groups. There was also a reduction in the incidence of major VTE (proximal DVT, nonfatal PE, and VTE-related death) by rivaroxaban in all four trials compared with the enoxaparin regimens; this attained statistical significance in RECORD3 for TKA (P = .01).

Apixaban

Apixaban is also an oral direct factor Xa inhibitor evaluated in phase III trials for the prevention of VTE after TKA or THA. In the phase III ADVANCE-1 study in TKA,²¹ there were 3195 patients randomized to receive apixaban, 2.5 mg twice daily, or enoxaparin, 30 mg twice daily. Both agents were administered 12 to 24 hours postoperatively and continued until days 10 to 14. The primary efficacy outcome of DVT, PE, and all-cause mortality occurred in 9.0% of patients receiving apixaban and 8.8% of patients receiving enoxaparin (P = .06). Rates of major bleeding with apixaban were numerically lower than with enoxaparin (0.7% vs. 1.4%), but this just failed to reach statistical significance. ADVANCE-2 was also in patients undergoing TKA and compared apixaban, 2.5 mg twice daily, with enoxaparin, 40 mg once daily, in 3057 randomized patients. The primary efficacy outcome occurred in 15.1% of patients in the apixaban group and 24.4% in the enoxaparin group, which was statistically significant (P < .001). There was no significant difference in major or clinically relevant nonmajor bleeding (3.5% and 4.8% of patients, respectively).

Rivaroxaban and dabigatran have been shown to have predictable pharmacokinetics and pharmacodynamics ^17,²⁹ and therefore do not need anticoagulation monitoring, as is required for VKAs.

There are many other small antithrombotic molecules, including a new generation of low LMWHs, which are currently in different stages of clinical development. These will further broaden the range of pharmacologic agents available for VTE prophylaxis in the future.

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