Clinical risk factors
Hematologic abnormalities
Prior venous thromboembolic disease
Antithrombin III deficiency
Advanced age
Disorders of plasminogen
Obesity
Protein C or protein S deficiency
Trauma (pelvis, hip, femur, tibia fracture)
Myeloproliferative disorder
Prolonged immobility
Heparin-induced thrombocytopenia
Coronary artery disease
Factor-V Leiden mutation
Congestive heart failure
Antiphospholipid syndrome and Lupus anticoagulant
Myocardial infarction or stroke
Hypertension
Malignancy
ASA score ≥3
Oral contraceptives or hormone replacement
Varicose veins
Many studies have attempted to identify specific clinical risk factors that increase the likelihood of postoperative VTE after THA. However, reproducibility of these risk factors has been limited, largely due to variations in the diagnosis and definition (symptomatic versus nonsymptomatic) of VTE. The most commonly agreed upon clinical risk factors include increasing body mass index, and history of a prior VTE episode [19–27]. Age greater than 70 or 75, cancer, cardiovascular disease, diabetes, hypertension, hormone replacement therapy, peripheral vascular disease, varicose veins, and a history of blood clotting disorders are potential clinical risk factors for VTE complications [8, 18, 19, 25–29].
In patients with a history of blood clotting disorders, there may be a genetic component and a thorough family history must be obtained. Several studies have found higher rates of VTE after THA in patients with high homocysteine levels, Factor-V Leiden mutation, antiphospholipid antibody syndrome, protein-C or S deficiency, antithrombin III deficiency, and prothrombin promoter G20210A mutation [19, 26, 30, 31].
Intraoperative Risk Factors
Intraoperative events during THA significantly impact the components of Virchow’s triad and contribute to the risk of postoperative VTE complications. Venous capacitance and outflow may be reduced during THA, resulting in subsequent venous stasis; leg positioning for exposure may further exacerbate stasis [32]. Endothelial injury may occur during manipulation of the extremity during dislocation of the hip or insertion of the prosthesis and the endothelium may suffer thermal injury from bone cement’s exothermic reaction [33, 34]. Lastly, hypercoagulability is markedly increased due to the release of several prothrombotic factors during soft tissue dissection and subsequent preparation and insertion of the femoral component [35].
Several studies have attempted to identify modifiable intraoperative risk factors for postoperative VTE complications, and particular emphasis has been placed on the type and duration of anesthesia utilized. Regional versus general anesthesia may result in lower risk of postoperative VTE because the sympathetic blockade secondary to regional anesthesia may result in vasodilation, increased blood flow, and, theoretically, less venous stasis. However, the actual benefit of regional anesthesia has not been definitively determined with regard to VTE complications and recent systematic reviews suggest there is no benefit [26, 36–39]. Duration of the anesthesia may also have an impact on the incidence of postoperative VTE [40, 41].
Postoperative Risk Factors
Prevention
Clinical practice guidelines established by professional organizations have been present for over 25 years, providing VTE prophylaxis recommendations after THA. The Surgical Care Improvement Project (SCIP) and Joint Commission on Accreditation of Healthcare Organization (JCAHO) mandate that some form of VTE prophylaxis be implemented postoperatively for THA patients, but do not recommend a specific prophylaxis regimen. The most commonly referenced guidelines are those published by the American College of Chest Physicians (ACCP) and the American Academy of Orthopaedic Surgeons (AAOS) [18].
The ACCP first established VTE prophylaxis guidelines in 1986 and frequently updates them, with the most recent being in 2012 [43]. For some time, the orthopedic community had significant concerns regarding these guidelines because there was an increased emphasis on efficacy of a prophylaxis regimen and limited focus on safety [44]. The most recent guidelines published in 2012 demonstrated that the ACCP had clearly listened to the concerns of the orthopedic community. The ACCP recommended a variety of chemoprophylaxis regimens including aspirin and portable mechanical compression devices, which were designated as acceptable when compared to no prophylaxis at all. The ACCP guidelines did not differentiate between total hip and knee arthroplasty regarding selection of an appropriate prophylaxis regimen.
In response to the guidelines established by the ACCP, the AAOS published their first VTE prevention guidelines in 2007 and, most recently, a second version in 2011 [26]. In this guideline, the AAOS panel did not recommend a specific prophylaxis agent or duration.
Currently, the orthopedic surgeon has a multitude of pharmacologic and/or nonpharmacologic VTE prophylaxis options available after THA. The selection of a prophylaxis regimen is a balance between efficacy and safety. The ideal regimen is highly patient-dependent and must consider each patient’s individual risk of VTE formation, postoperative bleeding, or other complications from VTE prophylaxis. The risks, benefits, and best available evidence (Table 6.2) of the most commonly used VTE prophylaxis modalities will be further discussed in the following sections.
Table 6.2
Summary of results from clinical trials comparing lovenox with new anticoagulant agents after total hip arthroplasty
Study | Dosage | Total deep venous thrombosisa | Total pulmonary embolism | Major bleeding complications |
|---|---|---|---|---|
Colwell et al. [45] | ||||
Enoxaparin | 30 mg BID | 3.2% | 1.0% | 1.2b% |
Warfarin | INR 2–3 | 3.1% | 0.8% | 0.5b% |
Record I [46] | ||||
Enoxaparin | 40 mg daily | 3.4%b | <0.1% | <0.1% |
Rivaroxaban | 10 mg daily | 0.8%b | 0.3% | 0.3% |
Record II [47] | ||||
Enoxaparin | 40 mg daily | 8.2%b | 0.5% | <0.1% |
Rivaroxaban | 10 mg daily | 1.6%b | 0.1% | <0.1% |
Advance III [48] | ||||
Enoxaparin | 40 mg daily | 3.6%b | 0.2% | 0.7% |
Apixaban | 2.5 mg BID | 1.1%b | 0.1% | 0.8% |
Re-novate [49] | ||||
Enoxaparin | 40 mg daily | 6.3% | 0.3% | 1.6% |
Dabigatran | 220 mg daily | 4.6% | 0.4% | 2.0% |
Dabigatran | 150 mg daily | 7.2% | <0.1% | 1.3% |
Re-novate II [50] | ||||
Enoxaparin | 40 mg daily | 8.6% | 0.2% | 0.9% |
Dabigatran | 220 mg daily | 7.6% | <0.1% | 1.4% |
Ephesus [51] | ||||
Enoxaparin | 40 mg daily | 9.0%b | 0.2% | 2.6% |
Fondaparinux | 2.5 mg daily | 4.0%b | 0.2% | 4.1% |
Pentathlon [52] | ||||
Enoxaparin | 30 mg BID | 8.2%b | 0.1% | 1.0% |
Fondaparinux | 2.5 mg daily | 5.6%b | 0.4% | 1.8% |
Pharmacologic Prophylaxis
A complete understanding of the physiologic coagulation cascade is essential to understand how each of the following six classes of VTE chemoprophylaxis agents executes its antithrombotic effect: vitamin K antagonists, low molecular weight heparins (LMWH), factor Xa inhibitors, antiplatelet agents, pentasaccharides, and direct thrombin inhibitors (Fig. 6.1).
Fig. 6.1
Coagulation cascade and the sites of action of commonly used anticoagulants . Red arrow = inactivation; Green arrow = activation; Orange boxes = Vitamin K-dependent factors sensitive to Warfarin (Modified with permission from Leung KH, Chiu KY, Fan CH, Ng FY, Chan PK. Review article: venous thromboembolism after total joint replacement. J Orthop Surg. 2013;21(3):351–60)
Vitamin K Antagonists
Warfarin continues to remain one of the most commonly utilized agents to prevent VTE events postoperatively largely due to its long track record [53]. It acts by preventing the carboxylation of glutamic acid on clotting factors II, VII, IX, X and cofactors C and S. It is orally dosed and titrated to a target goal for the international normalized ratio (INR). The ACCP recommends a range of 2–3 while the AAOS recommends a goal INR of two or less [26, 43]. A number of randomized trials have compared warfarin to LMWH and have demonstrated higher overall VTE rates in patients treated with warfarin. However, symptomatic VTE rates between the two groups are similar and postoperative bleeding complications are generally lower in the warfarin group [45, 54, 55]. The major advantages of warfarin are that it is an oral agent and the level of anticoagulation can be titrated, but its use is limited by the need for frequent INR monitoring and interactions with other medications and food products .
Low Molecular Weight Heparins
LMWH functions by binding to antithrombin III (AT III), which accelerates the subsequent inactivation of thrombin and factor Xa. LMWH is administered through a subcutaneous injection and requires no monitoring . Currently, LMWH is the most commonly used prophylactic agent for VTE after THA worldwide [53]. Its efficacy has been well documented in numerous randomized trials, including those comparing it to warfarin as previously discussed. Several other studies have compared the efficacy of LMWH to newer antithrombotic agents that will be discussed later in this chapter. The dosing of LMWH is either 40 mg once daily (European regimen) or 30 mg twice daily (North American regimen). The limitations of LWMH stem from concerns about post-discharge patient compliance regarding subcutaneous injections, its relatively high cost compared to warfarin or aspirin, and surgeon concern about increased postoperative bleeding risk .
Direct Factor Xa Inhibitors
Factor Xa inhibitors directly and reversibly inhibit factor Xa, which catalyzes the conversion of prothrombin to thrombin. In the United States there are currently two factor Xa inhibitors available for VTE prophylaxis after THA: apixaban and rivaroxaban. Edoxaban is a third agent currently approved in Japan for VTE thromboprophylaxis following major orthopedic surgery, but its use in the United States following THA is pending phase III trial results. The ACCP recommends the use of Apixaban/Rivaroxaban (grade IB) in patients undergoing major orthopedic surgery.
Apixaban is orally administered at 2.5 mg twice daily and rivaroxaban is orally administered at a dose of 10 mg daily. In randomized trials, both agents have demonstrated greater efficacy in preventing VTE after THA in comparison to LMWH, without increased risk of postoperative bleeding [46–48]. The major concern with the use of these Factor Xa inhibitors is the risk of postoperative bleeding and some orthopedic surgeons elect to administer the drug off label, 18–24 h after surgery, to help minimize this risk .
Antiplatelet Agents
Aspirin functions by irreversibly inactivating cyclooxygenase’s formation of thromboxane A2 in platelets, thus inhibiting platelet function. Interest in aspirin for VTE prophylaxis after THA has grown over the past decade as evident by recent changes in the ACCP guidelines [34, 44]. In the 8th edition of the ACCP guidelines, a grade IA recommendation was made against the use of aspirin as a thromboprophylaxis agent [56]; however, in the most recent 9th edition, a grade IB recommendation was made for the use of aspirin as a prophylactic VTE agent following major orthopedic surgery when compared to no prophylaxis at all [43]. The SCIP guidelines accordingly changed and now include aspirin as an acceptable agent for VTE prophylaxis following THA.
These recent changes in national guidelines were largely driven by results of the Pulmonary Embolism Prevention (PEP) trial which demonstrated a significant difference between aspirin and placebo, without an increase in bleeding complications, with respect to VTE complications in all patients with a hip fracture and those patients with a hip fracture managed with arthroplasty [57]. Unfortunately, the study was underpowered to evaluate the efficacy of aspirin in patients undergoing elective THA. Whether or not aspirin is as effective in reducing VTE complications after THA in comparison to other agents remains controversial as nonrandomized studies have demonstrated differing results from the PEP trial [7]. In a report by Jameson et al. [58] from the National Joint Registry for England and Wales for THA , overall efficacy was the same for LMWH and aspirin and bleeding rates were also the same. The selection of a prophylaxis agent is a balance between efficacy and safety. Aspirin is likely not as powerful an anticoagulant as other available chemoprophylaxis agents, but the major benefits of aspirin include its oral dosing, high rate of patient compliance, and perceived lower risk of bleeding [57, 59–61]. The optimal dose for aspirin in VTE prophylaxis has not been identified, but the most commonly prescribed dose is 325 mg twice daily for 6 weeks .
Pentasaccharides
Fondaparinux is a synthetically manufactured polysaccharide that inactivates factor Xa by causing a conformational change in AT III, which increases the binding of AT III to factor Xa. It is administered subcutaneously and its overall efficacy is similar to that of LMWH [51, 52]. It is typically injected at 2.5 mg once daily in patients greater than 50 kg without a history of renal insufficiency. A possible advantage of fondaparinux over LWMH is its potentially lower rate of heparin-induced thrombocytopenia (HIT) and its use in patients already diagnosed with HIT [62]. However, concerns regarding postoperative bleeding complications have limited the use of fondaparinux [63].
Direct Thrombin Inhibitors
Dabigatran etexilate is orally administered and directly binds to the active catalytic site on thrombin, reversibly inhibiting it. Dabigatran was previously approved only for prevention of stroke or atrial fibrillation, but in 2014 the Food and Drug Administration (FDA) approved its use for secondary prevention of DVTs and PEs. The ACCP recommends its use (grade IB) in patients undergoing major orthopedic surgery. Dabigatran is typically administered once daily at doses of either 150 mg or 220 mg and both doses have demonstrated similar efficacy to LWMH in preventing VTE complications after THA without increasing postoperative bleeding complications [49, 64].
Nonpharmacologic Prophylaxis
Mechanical Prophylaxis
Recently, increased interest in pneumatic compression devices for VTE prophylaxis following THA has developed due to the development of mobile compression devices that can be used after hospital discharge [44]. The use of pneumatic compression devices is predicated on the physiological concept that compression of the lower extremity venous system decreases venous stasis, increases local blood flow, and increases local, but not systemic, fibrinolysis [50, 65]. The efficacy of these devices in preventing VTE after THA has been assessed since the 1980s, but conclusions have been limited by the quality of these studies. Initial studies demonstrated pneumatic compression devices to be inferior to warfarin in preventing VTE formation after THA [66–68]. More recent studies comparing LWMH to the use of a foot pump or mobile compression device suggest similar efficacy between the two modalities but these studies were underpowered [69, 70].
The aforementioned results led to the ACCP recommending (grade IC) mobile pneumatic compression devices as a stand-alone measure for VTE prophylaxis after THA only if worn for at least 18 h per day [43, 71]. The obvious advantage of these mechanical compression devices is the absence of postoperative bleeding risk, but mechanical prophylaxis is typically discontinued at the time of discharge and given recent decreases in inpatient stay after THA, this could lead to inadequate prophylaxis. The development of portable mechanical compression devices has helped mitigate this issue and recently published studies demonstrate promising results [71]. However, the cost of these devices and continued concerns regarding post-discharge compliance have limited their use.
Decreased venous stasis and increased regional blood flow can also be achieved through postoperative ambulation. Some studies have demonstrated a significant decrease in postoperative VTE complications in patients who ambulated early in the postoperative period [13]. The AAOS makes a consensus recommendation for early mobilization after THA given its potential efficacy, minimal cost, and low risk [26].
Inferior Vena Cava (IVC) Filters
Patients undergoing THA who have increased risk for both PE and major bleeding, contraindications to chemoprophylaxis, or recurrent PE despite therapeutic chemoprophylaxis may be considered for IVC filter placement [72]. When placed, these filters have the ability to block the passage of emboli from the lower extremity venous system to the pulmonary circulation. However, there have been no randomized studies assessing the primary prevention efficacy of IVC filters in preventing PEs. Therefore, the ACCP does not recommend (grade 2C) the use of an IVC filter as primary prophylaxis as opposed to no thromboprophylaxis at all in patients with high risk for both PE and bleeding [43]. The AAOS makes an inconclusive statement about the use of IVC filters in this same patient population [26]. The concern is that IVC filters may not reduce symptomatic PE rates and that chronic disease may develop if filters are left in place [73, 74].
Duration of Prophylaxis
The exact duration of VTE prophylaxis following THA has not been definitively established but there is general agreement that prophylaxis should start on the day of surgery and continue for at least 10–14 days [16]. However, extended duration of VTE prophylaxis, up to 35 days, has demonstrated significant decreases in VTE complications as well [75–79]. Currently, the ACCP provides a grade IB recommendation for 10–14 days of prophylaxis and a grade 2B recommendation for extended prophylaxis up to 35 days, while the AAOS does not provide a specific duration recommendation [26, 43]. The ideal duration for postoperative VTE prophylaxis remains highly patient-dependent and most surgeons base their duration on perioperative risk factors for VTE complications after THA [18, 34].
Summary of VTE Prevention
The selection of an ideal postoperative VTE prophylaxis regimen after THA is of paramount importance in the perioperative management of arthroplasty patients. As the total number of THAs performed annually continues to grow, particularly in patients with greater clinical risk factors for VTE, an effective and safe prophylactic regimen that minimizes VTE complications without significantly increasing postoperative bleeding complications must be selected in a patient-dependent manner. Further research is needed to develop more effective risk stratification strategies, allowing for appropriate anticoagulation strength and duration, while minimizing chemoprophylaxis complications. An ideal prophylaxis regimen seeks to prevent symptomatic VTE events while limiting bleeding and other wound complications .
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