1. Identify the incidence of postoperative DVT following total joint replacement

Venous thromboembolism (VTE) causes morbidity and mortality in orthopedic patients with an incidence that remains underestimated [1]. Without active prophylactic treatment, the incidence of VTE among patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA) may reach 60 and 85%, respectively [2–3]. Appropriate pharmacologic thromboprophylaxis reduces VTE in hospitalized patients to only 1.1% after TKA and 0.5% following THA [4]. Further, pharmacologic thromboprophylaxis has reduced the incidence of pulmonary embolism (PE), a possibly catastrophic manifestation of VTE, from 2.2% to 0.2% [3]. However, the risk of VTE extends for several weeks following surgery, with most cases occurring after hospital discharge [5–7]. Consequently, VTE prophylaxis should be extended up to 35 days after orthopedic surgery [8].

2. Describe the morbidity and mortality associated with DVT

Adverse events (AEs), the majority of which are preventable, occur in approximately 3% of hospital admissions [9]. Venous thromboembolism is one of the most serious AEs following orthopedic surgery. In a recent study of 60,000 patients, AEs in surgical patients increased while VTE rates declined [10]. This is potentially due to quality improvement and thromboprophylaxis utilization [10].

Despite published and recognized guidelines, the universal VTE prophylaxis implementation remains lacking. The 2012 American College of Chest Physicians (ACCP) guidelines recommend that both THA and TKA patients receive anticoagulant prophylaxis postoperatively for a minimum of 10, and up to 35, days [1]. However, a study of 70,000 hospitalized patients, including those at high risk for VTE, found that appropriate prophylaxis treatment was administered in only 59% of patients [11]. Subgroup analysis revealed that only 88% of orthopedic patients received an appropriate prophylaxis regimen during inpatient hospitalization [11]. Similarly, Selby et al. evaluated postoperative thromboprophylaxis in total joint arthroplasty patients showing appropriate treatment in only 40% of patients; notably, most deviations were noted after hospital discharge [12]. Furthermore, failure to receive thromboprophylaxis for a minimum of ten days was associated with a higher incidence of symptomatic VTE, without differences in bleeding rates, as compared to ACCP-aligned patients [12].

3. Analyze how general versus regional anesthetic techniques impact the incidence of DVT

In 2000, Rodgers et al. published a meta-analysis that reported reduced mortality at 30 days when comparing intraoperative neuraxial blockade to general anesthesia [13]. A total of 365 DVTs were reported, with 80% from orthopedic trials; neuraxial blockade reduced the risk of DVT by almost half [13]. Unfortunately, these results have been questioned because the majority of studies that were included in the analysis occurred prior to the routine use of pharmacological VTE prophylaxis [13]. Recently, Neuman et al. [14] evaluated the association of anesthesia technique with 30-day mortality among patients undergoing hip fracture surgery and did not demonstrate a lower 30-day mortality with regional compared to general anesthesia; however, regional anesthesia was associated with a shorter length of stay. Although, these findings do not show that decreased mortality occurs with neuraxial anesthesia, regional techniques still remain an adjuvant in reducing VTE risk by treating postoperative pain and facilitating faster rehabilitation.

Multimodal pathways that utilize regional anesthesia to improve acute postoperative pain must allow for VTE prophylaxis [15–17]. Epidural postoperative analgesia had been widely used in orthopedic patients. Its success mainly derives from the previously demonstrated decreases in surgical blood loss and opioid consumption. While benefits have been noted, continuous neuraxial techniques have been associated with spinal hematoma, most often in the anticoagulated patient. Consequently, caution must be used with neuraxial anesthesia in patients receiving thromboprophylaxis [18]. In patients undergoing THA or TKA, peripheral nerve blocks are effective and safe alternatives to neuraxial anesthesia and analgesia [19–22]. Since guidelines have focused on complications from anticoagulants with neuraxial techniques rather than peripheral nerve blocks (PNBs) [18], several publications have attempted to evaluate the risks of PNBs in patients receiving anticoagulants. Minor bleeding from vessel trauma is the most common hemostatic complication, although case reports have described major hemorrhage [23–27]. In trauma patients with PNBs who receive thromboprophylaxis, no hemorrhagic complications were noted in 305 perineural catheters [28]. In another study of 6,935 PNBs after major orthopedic surgery, no cases of perineural hematoma were noted [29]. Furthermore, a retrospective evaluation of 617 THA patients undergoing continuous lumbar plexus infusion and receiving warfarin thromboprophylaxis found no major bleeding, despite 36% of patients having an INR >1.4 at the time of catheter removal [30]. These findings were recently confirmed by another series of 316 patients with lumbar plexus catheters and INR values up to 4.0 [31]. Despite these reports, the American Society of Regional Anesthesia (ASRA) advises that caution should be exercised when combining deep blocks with antithrombotic prophylaxis because of the increased risk of major bleeding [18]. Some have suggested that peripheral nerve blocks in the setting of thromboprophylaxis may be appropriate in the absence of other hemostatic concerns based on the paucity of evidence suggesting a relative contraindication [32].

4. Review non-pharmacologic interventions used to prevent postoperative DVT

The ideal prophylactic regimen to prevent VTE after major orthopedic surgery is currently based on the combination of anticoagulants together with mechanical prophylaxis [33]. It has been suggested that decreasing intraoperative blood loss through both adequate surgical hemostasis and controlled hypotension may reduce patients’ perioperative hypercoagulative state [34]. Perioperative fluid management targeted to avoid hematic concentration may also decrease VTE risk [35].

Patient inactivity in the perioperative period increases the risk of DVT approximately ten-fold. Passive and active movement in bed, use of compression stocking or intermittent pneumatic compression devices, and early mobilization out of bed are associated with a lower VTE risk. Consequently, effective pain management that facilitates rehabilitation and ambulation is mandatory [36–37]. Additionally, ACCP guidelines recommend combining antithrombotics with intermittent pneumatic compression devices, suggesting the use of portable battery powered devices that are capable of recording daily wear time, with the goal of 18 h/day [1].

5. List common pharmacologic DVT prophylaxis regimens for total joint replacement

Adequate pharmacologic prophylaxis is essential in reducing the morbidity and mortality related to VTE in the orthopedic patient. Until 2008, clinicians’ choices for anticoagulant to prevent VTE in patients undergoing THA or TKA were limited to unfractionated heparin (UFH), low molecular weight heparin (LMWH), fondaparinux, and warfarin [3]. Since then, direct factor Xa inhibitors, rivaroxaban and apixaban, and a direct thrombin inhibitor, dabigatran, have become options for patients undergoing major orthopedic surgery (Table 23.1).

Although effective, warfarin, a vitamin K antagonist, has numerous limitations including variable dose responses, the need for laboratory monitoring, significant drug and food interactions, and a relatively long time to achieve therapeutic anticoagulation [38–39].

UFH and LMWH function as anticoagulants by binding to antithrombin (AT3) and accelerating its inhibitory activity against thrombin and factor Xa [40]. Low molecular weight heparin is generally administered subcutaneously without lab monitoring and is widely used in orthopedic patients [1]. Enoxaparin is used for VTE prophylaxis at either the subcutaneous dosage regimen of 40 mg once daily starting 12 hours preoperatively or 30 mg twice daily starting 12 to 24 hours postoperatively. A recent indirect comparison of the two enoxaparin regimens in patients undergoing major orthopedic surgery suggests that enoxaparin 30 mg twice daily is more effective than enoxaparin 40 mg daily in preventing VTE, but it was also characterized by an increased risk of major bleeding [41].

Fondaparinux, a synthetic polysaccharide parenteral anticoagulant, binds to the heparin-binding site on AT3 and catalyzes AT3-mediated inhibition of factor Xa [42]. The drug has a longer half-life (17–21 h) compared with LMWH and is administered subcutaneously at the fixed dose of 2.5 mg daily for the prevention of VTE after THA and TKA.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic state that can complicate the use of heparin. Although the risk is ten-fold greater with UFH, LMWH is also associated with HIT [43–45]. Fondaparinux has been associated very rarely with HIT and has been used in a number of cases to treat HIT [46].

The ideal anticoagulant should be orally administered, target a single enzyme in the coagulation cascade, require no monitoring, have minimal drug–drug and drug–diet interactions, not cause thrombocytopenia, and have a low risk of bleeding. The development of new oral anticoagulants (NOACs) has focused on inhibiting thrombin and factor Xa, given their central role in the coagulation cascade.

Rivaroxaban is an oral, direct, and selective inhibitor of factor Xa, both in its free and prothrombin-bound forms [47]. It is approved in Europe and the United States for VTE prophylaxis in patients undergoing elective hip or knee replacement at the dosage of 10 mg/day, starting no sooner than six to ten hours postoperatively once hemostasis has been achieved. The Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism (RECORD) program compared rivaroxaban with enoxaparin in four randomized, double-blind phase III trials and concluded that rivaroxaban was superior to enoxaparin in thromboprophylaxis after major orthopedic surgery with a similar safety profile [48–51].

Dabigatran etexilate is an orally active prodrug that is converted to the active direct thrombin inhibitor, dabigatran [52]. At the dosages of 150 to 220 mg/day, it was approved in Europe in 2008 for primary prevention of VTE in adult patients who have undergone elective hip or knee replacement. The first dose of dabigatran should be administered one to four hours after surgery, at half of the total daily dose, once hemostasis has been achieved. Dabigatran is not FDA approved for this indication since in the RE-MOBILIZE study dabigatran was inferior to the North American regimen of subcutaneous enoxaparin 30 mg twice daily [53].

Apixaban is an oral, direct, and selective factor Xa inhibitor indicated for the prevention and treatment of VTE [54]. Apixaban typically reaches maximal plasma concentration within 1 to 3.5 hours and has a half-life similar to that of LMWH (12 h) [55]. It is approved in Europe and the United States for the prevention of VTE after THA and 2.5 mg twice daily is recommended to start 12 to 24 h after wound closure [56].