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Unanswered Questions, Unmet Needs in Venous Thromboprophylaxis

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Abstract

Although significant progress has been made over the past 25 years in preventing thromboembolic disease in patients undergoing total hip and total knee arthroplasty, important questions remain unanswered. Few would debate the need to seek a balance between maximal antithrombotic efficacy and minimal bleeding in choosing a thromboprophylactic strategy, but there is less agreement as to how efficacy should be defined, and whether efficacy and safety (however each is defined) are intrinsic to the thromboprophylactic agent chosen or depend as well on exogenous factors, ranging from the timing of drug administration to surgical technique. Differences between recent guidelines from the American Academy of Orthopaedic Surgeons (AAOS) and the American College of Chest Physicians (ACCP) illustrate these unanswered questions. The AAOS guidelines focus solely on preventing symptomatic pulmonary embolism and ignores the importance of other acute and chronic manifestations of venous thromboembolic disease. The ACCP, on the other hand, does consider these other manifestations of venous thromboembolic disease, and thus reaches very different conclusions about what constitutes effective thromboprophylaxis. Despite these questions and uncertainties, there are fundamental truths: (1) venous thromboembolism (VTE) is a known and serious complication of total joint arthroplasty, and (2) evidence-based thromboprophylaxis works. Gaps between guideline-recommended and actual orthopedic practice must be reduced.

For the past 30 years, orthopedic surgeons have balanced the need to prevent venous thromboembolism (VTE) with the need to avoid other complications following total joint arthroplasty. Despite continuous effort and much progress, important questions have yet to be answered regarding how best to achieve this balance. For example, thromboprophylaxis guidelines from the American College of Chest Physicians (ACCP) and the American Academy of Orthopaedic Surgeons (AAOS) differ regarding the importance of deep venous thrombosis (DVT) and of asymptomatic pulmonary embolism (PE). The value added by new pharmacotherapies and novel means of mechanical prophylaxis remains to be defined. Which approach to thromboprophylaxis affords the best balance between safety and efficacy remains an unanswered question.

Preventing VTE: The Trade-off Between Efficacy and Safety

The rate of DVT is unacceptable without thromboprophylaxis. Venographic studies in the absence of thromboprophylaxis show that the DVT rates range from 45% to 57% for total hip arthroplasty (THA) and from 40% to 84% for total knee arthroplasty (TKA).^1,2 Proximal clot, which is associated with a higher rate of PE, occurs in from 23% to 36% of THAs and from 5% to 22% of TKAs.²

Early studies comparing unfractionated heparin and low-molecular-weight heparin (LMWH) for thromboprophylaxis following THA showed that LMWH reduced the incidence of VTE without increasing the incidence of major bleeding.^3-7 When the LMWH enoxaparin was compared with warfarin for thromboprophylaxis in the setting of THA, there was a significant 6% reduction in the absolute risk of venographic DVT with enoxaparin (31.4% vs. 37.4%; P=.03); however, enoxaparin was associated with a significant 1.5% absolute increase in the risk of major bleeding (1.2% vs. 2.8%; P=.04).

This trade-off between thromboprophylactic efficacy and bleeding became even clearer in studies of TKA. In a double-blind prospective study involving 670 consecutive patients undergoing TKA, Leclerc et al⁸ compared enoxaparin (30 mg subcutaneously every 12 hours) with warfarin (international normalized ratio [INR], 2.0-3.0) for thromboprophylaxis. Each agent was initiated postoperatively: warfarin was given in the evening on the day of surgery and enoxaparin was given in the morning of the first day after surgery. Treatment continued for 14 days or until hospital discharge, whichever came first. Bilateral venography demonstrated that despite prophylaxis, VTE developed in 36.9% of patients on enoxaparin and 51.7% of patients on warfarin (P=.003). Rates of proximal clot were lower but not significantly different: 11.7% for enoxaparin compared with 10.4% for warfarin. Risk of bleeding was comparable in the 2 groups, with major bleeding occurring in approximately 2% of patients.

Fitzgerald et al⁹ also compared enoxaparin and warfarin for thromboprophylaxis in 349 patients undergoing TKA. In this open-label study, prophylaxis was initiated within 8 hours following surgery and continued for 4 to 14 days. VTE was defined as (1) DVT identified on contrast venography, (2) symptomatic DVT identified on lower extremity ultrasonography, or (3) symptomatic, objectively confirmed PE. A significant decrease in the incidence of VTE was seen with early postoperative dosing: total VTE was 25% in the enoxaparin group and 45% in the warfarin group (P=.0001). Even more impressive was that early dosing of enoxaparin nearly eliminated proximal VTE, which occurred in 1.7% of enoxaparin- vs. 11.4% of warfarin-treated patients (P=.002). In contradistinction, proximal DVT occurred in nearly 12% of enoxaparin-treated patients in the study by Leclerc et al.⁸

The early postoperative dosing of enoxaparin did not result in a statistically significant increase in the incidence of major bleeding when compared with warfarin treatment (3% for enoxaparin vs. 7% for warfarin), but the rate of overall hemorrhagic complications (including clinically important operative site hemorrhage) was higher in the enoxaparin group (6% for enoxaparin vs. 3% for warfarin).

The Fitzgerald study demonstrated how a simple modification of the timing of intervention could affect the efficacy and safety profile of a given agent. By beginning chemoprophylaxis within 8 hours of surgery, there was less DVT formation but at the expense of a trend toward more bleeding events. Questions remain with all pharmacologic DVT prophylaxis with regard to the optimal dose, the timing of intervention, and whether advantages observed with any given agent should be ascribed to its intrinsic pharmacologic properties or to the specific dosing regimen.

Remaining Uncertainties

One of the major remaining uncertainties in thromboprophylaxis is the likelihood that any given pharmacologic approach will cause bleeding. Such uncertainties are derived, in part, from conflicts in the literature. Keeney et al¹⁰ described their institution’s experience with trimodality prophylaxis for primary and revision hip arthroplasty. Adjusted-dose warfarin for 7 days (target INR, 2.0-2.5), pneumatic compression, and early mobilization were used in 700 patients, with bilateral lower extremity venous ultrasonography performed on postoperative day 3 or 4. With this regimen, there were no deaths, a 4.4% rate of DVT, a 0.1% rate of nonfatal PE (based on clinical examination and positive ventilation-perfusion scanning), and a 0.3% rate of bleeding. The same institution then adopted the ACCP 1A protocol for thromboprophylaxis with enoxaparin. Burnett et al¹¹ published the results of their study in 290 patients in whom this protocol was used. The study was terminated early because of an unacceptable rate of complications, primarily bleeding, which occurred in 9% of patients receiving enoxaparin. Symptomatic DVT occurred in 4% of patients, whereas PE occurred in 1.3%. Additionally, 5% of patients required readmission and 3.5% were returned to the operating room for wound complications. The rate of wound complications requiring operative intervention was 3 times higher than with the institution’s previous warfarin-containing protocol.

The results of the Burnett et al¹¹ study are markedly different from those of other recent studies, which show rates of major bleeding with enoxaparin ranging from 0.1% to 0.5% and rates of major VTE ranging from 2% to 2.6%.^12,13 For example, Lassen et al¹² recently compared enoxaparin with rivaroxaban in 2531 patients undergoing TKA. With enoxaparin, major VTE occurred in 2.6% of patients and major bleeding in only 0.5%. The safety and efficacy of enoxaparin in these recent large studies appear quite favorable.

Safety as an Operator-dependent Variable

These results with enoxaparin mirror our experience in both THA and TKA, and suggest that the relative safety and efficacy of particular approaches to chemoprophylaxis might in part be operator-dependent. For example, we have not seen significant problems with wound healing, drainage, or hematoma formation with enoxaparin using a multimodal approach to perioperative management. We take several steps to minimize bleeding and wound complication. First, an injection of 30 mL 1% lidocaine with epinephrine along the arthrotomy site reduces intraoperative bleeding and the postoperative decrease in hemoglobin, and therefore may reduce postoperative bleeding complications.¹⁴ Then, meticulous intraoperative hemostasis is ensured prior to wound closure. At the end of the case, a fibrin sealant is applied, which in TKA has been shown to reduce postoperative blood loss and rates of allogeneic transfusion.^15,16 Starting enoxaparin 18 to 24 hours after surgery falls within the 12- to 24-hour window specified in the ACCP guideline,² but allows hemostasis to occur before anticoagulation. In the meantime, sequential compression devices and graduated compression stockings protect the patient immediately postoperatively and later act as an adjunct to chemoprophylaxis. A “watertight” closure of the arthrotomy and subcutaneous tissues is essential to prevent wound drainage and hematoma formation. An intra-articular reinfusion drain further prevents hemarthrosis while preserving the patient’s blood and reducing the need for allogeneic transfusion. Finally, use of a continuous passive motion machine is delayed until the next day so as not to interrupt hemostasis.

When drain output or postoperative bleeding is greater than anticipated, several steps can be taken to achieve hemostasis and reduce further blood loss or wound drainage. Following TKA, flexing the knee for a short period of time often significantly improves hemostasis. In addition, the drain can be clamped, physical therapy can be delayed, or continuous passive motion can be discontinued. The most important immediate goals following joint arthroplasty are to maintain a dry wound and prevent hemarthrosis.

As with most aspects of surgery, the surgeon needs to define a protocol that works for his or her patients. The earlier chemoprophylaxis is administered, the lower the VTE rate; however, this must be weighed against an increase in the potential for bleeding and the risk of wound complication. Recently, Patel et al¹⁷ evaluated 2437 total joint arthroplasties (both primary THAs and TKAs) to identify risk factors associated with prolonged wound drainage. Following THA, increased wound drainage was associated with morbid obesity, the use of LMWH, and increased drain output. However, prolonged wound drainage in TKA was only associated with increased drain output. In this study, each day of prolonged wound drainage increased the risk of infection by a remarkable 42%. Other factors that may contribute to bleeding and wound complication include failure to use a postoperative drain, the use of ketorolac or other nonsteroidal anti-inflammatory drugs for pain control, and particular surgical techniques such as soft tissue release during TKA. Large medial or lateral releases performed during surgery will result in more bleeding, bruising, swelling, and occasionally a subcutaneous hematoma formation or fluid collection. These factors need to be considered when choosing an agent for thromboprophylaxis for a specific patient as well as when evaluating patients with regard to potential complications from thromboprophylaxis.

Comparing ACCP and AAOS Guidelines: Strengths and Weaknesses

That there are 2 conflicting guidelines for thromboprophylaxis in the setting of total hip and knee arthroplasty further complicates the decision-making process for surgeons. The ACCP guidelines (reviewed by Dr. Clifford W. Colwell Jr in this supplement) focus on minimizing the overall rate of VTE. Guidelines from the AAOS¹⁸ (reviewed by Dr. Paul Lachiewicz in this supplement) focus on preventing only symptomatic PE while minimizing rates of major bleeding and wound complications. It is important (1) to understand the different goals of these guidelines and (2) to understand that the AAOS guidelines are not recommendations for general thromboprophylaxis.

In addition to their focus on preventing all VTE, other strengths of the ACCP guidelines are that they provide recommendations concerning duration of prophylaxis, treatment of both symptomatic and asymptomatic DVT, the appropriate use of inferior vena caval filters, and how to prevent postphlebitic syndrome. With regard to both THA and TKA, grade 1A recommendations include the use of LMWH, fondaparinux, or warfarin (target INR: 2.5; range: 2-3). According to these guidelines, graduated compression stockings, intermittent compression devices, and other methods of mechanical thromboprophylaxis are less effective in preventing proximal DVT than anticoagulant-based strategies and cannot be recommended as primary means of thromboprophylaxis in THA. However, for patients at high risk for bleeding who are undergoing TKA, the optimal use of intermittent compression devices may be an alternative to anticoagulant thromboprophylaxis. The guidelines do not support the use of multimodal thromboprophylaxis because of the lack both of randomized clinical trials comparing such approaches to single modalities and of trials using contrast venography to measure efficacy. Finally for both hip and knee arthroplasty, the ACCP guidelines strongly recommend against using aspirin or low-dose unfractionated heparin as the only means of thromboprophylaxis.²

The AAOS guidelines also have several strengths. The pillars of the AAOS guidelines are that patients should be assessed preoperatively regarding the risk of DVT/PE and bleeding and be treated according to individual risk.¹⁹ As noted earlier, the goal of treatment according to the AAOS guidelines is to prevent symptomatic PE¹⁹; the AAOS rejects DVT as a valid endpoint for evaluating the efficacy of thromboprophylaxis, arguing that the relationship between DVT and PE is unproven. This approach may reduce overtreatment with anticoagulants and reduce the risk of major bleeding and wound complications. The AAOS guidelines allow the use of aspirin for all patients except those considered at high risk for PE and at standard risk for bleeding. In addition, the AAOS lowers the target INR to <2 for patients treated with warfarin. The AAOS categorizes patients into 4 groups based on risk of bleeding and PE. Patients who are at standard risk for PE and major bleeding can be treated with aspirin, LMWH, warfarin, or fondaparinux. Patients at high risk for PE and at standard risk for bleeding can be treated with LMWH, warfarin, or fondaparinux. Finally, any patient who is at elevated risk for bleeding can be treated with aspirin, warfarin, or without antithrombotic agents.¹⁸

When considering the 2 guidelines, several questions remain. Should the goal be to simply prevent symptomatic PE as in the AAOS guidelines, or should the goal be to prevent all forms of VTE as in the ACCP guidelines? What risk of major bleeding or wound complications is acceptable to prevent asymptomatic or clinically insignificant DVT? How useful are guidelines that depend on preoperative risk stratification when it is often not possible to predict which patients are at high risk during preoperative assessment? Are any arthroplasty patients truly at low risk of DVT/PE? Are sequential compression devices and aspirin reasonable recommendations for arthroplasty patients who are at high risk? Are the AAOS guidelines inappropriate for many (or indeed, the majority of) arthroplasty patients?

The rejection by the AAOS guidelines work group of the relationship between DVT and PE is questionable. Girard et al²⁰ demonstrated the presence of DVT in 82% of patients with acute PE. Additionally, Pellegrini et al²¹ reported on the progression of untreated DVT to PE in their John Charnley Award-winning paper. The bulk of the medical and surgical literature seems to support the ACCP position: in order to prevent PE, all VTE should be prevented. Moreover, numerous studies, including 1 meta-analysis, demonstrate rates of VTE with aspirin ranging from 47% to 72%²²; aspirin would thus appear inadequate as a thromboprophylactic agent. This raises additional concern regarding the AAOS guidelines.

Beyond the Guidelines

A major hurdle in thromboprophylaxis is that the orthopedic community frequently does not accept (or at least implement) either guideline. Although data do not exist concerning compliance with the AAOS guidelines, Friedman et al²³ recently reported on compliance with ACCP guidelines in 8160 arthroplasty patients in the United States. Although almost all received some form of recommended thromboprophylaxis, only 61% of those undergoing TKA and 47% of those undergoing THA received prophylaxis that was fully compliant with the ACCP guidelines. Remarkably, these patients were treated by a group of surgeons with a history of VTE research. Levels of compliance with the ACCP guidelines in the general orthopedic community may well be lower.

Defining the Role of Novel Pharmacotherapies

Another area of uncertainty in thromboprophylaxis is the role to be played by novel pharmacotherapies. In light of the drawbacks of standard therapies, it can reasonably be argued that such agents are necessary. For example, even though LMWH has proven efficacy, there are issues of cost, the need for injection, and the associated risks of bleeding and wound complication. Warfarin also has its disadvantages. It initially acts as a procoagulant and a therapeutic level of anticoagulation may not be achieved with warfarin until days following surgery or even until after hospital discharge. Monitoring warfarin is extremely difficult, requiring frequent blood draws. Finally, the use of warfarin requires significant patient education with regard to diet and potential drug interactions. Failure to control the former or prevent the latter can result in drastic fluctuations in the INR leading to catastrophic bleeding or thrombosis.

Novel pharmacotherapies may come to play an important role in thromboprophylaxis. Tranexamic acid, an antifibrinolytic agent that competitively inhibits the conversion of plasminogen to plasmin, may play a role in joint arthroplasty by reducing blood loss and aid in preventing wound complications (and thus perhaps increase the therapeutic window of anticoagulant thromboprophylaxis). Orpen et al²⁴ demonstrated in a prospective randomized study of 29 patients undergoing TKA that tranexamic acid reduces early blood loss without increasing the rate of VTE. Similar results have been seen in THA.²⁵ Tranexamic acid has been well-studied in cardiac surgery, but more studies in orthopedics are needed.

Rivaroxaban is an orally active direct factor Xa inhibitor (and is discussed further by Dr. Richard J. Friedman in this supplement). Rivaroxaban has been studied in more than 12,000 patients undergoing THA and TKA, and has been shown to be more effective than enoxaparin in preventing VTE without an associated increased risk of bleeding.^12,13,26,27 The role of rivaroxaban and other oral agents, such as dabigatran²⁸ and apixaban, if they come to market in the United States, remains to be defined.

Other Answered Questions

Mechanical prophylaxis and multimodal protocols are common and need to be further addressed in future trials. In clinical practice, surgeons are stacking modalities: aggressive physical therapy with mobilization, less invasive surgical techniques, mechanical devices, and anticoagulation are often combined. There are few evidence-based recommendations regarding stacking techniques. Whereas intermittent compression devices are accepted for use following TKA in patients at high risk for bleeding according to the ACCP guidelines,² the trend for earlier hospital discharge might increasingly impose practical limitations on their use. Recently, portable compression devices have become available. Even though they appear effective, compliance and mechanical failure may be issues.²⁹ Both mechanical and multimodal prophylaxis regimens need to be compared with single modalities in randomized clinical trials with venographic endpoints before they can be routinely recommended by the ACCP.

Finally, there is no consensus on which orthopedic patients—other than those undergoing total hip or knee arthroplasty or with hip fracture—need thromboprophylaxis. These include patients with fractures, low-energy trauma, extensor mechanism ruptures, or ligament reconstruction, and those undergoing knee arthroscopy. Future clinical trials (and guidelines) need to address these lower-risk patients.

Conclusion

Thus, many questions concerning how best to effect thromboprophylaxis in the orthopedic setting remain unanswered, and our (likely unobtainable) need for an ideal strategy combining complete efficacy with absolute safety remains unmet. However, we should not permit such questions and needs from obscuring fundamental truths made clear by intense research over the past several decades: (1) VTE is a known and serious complication of total joint arthroplasty; (2) evidence-based thromboprophylaxis works; (3) the orthopedic community can do better.

References

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Authors

Drs Cushner and Nett are from the Insall Scott Kelly Institute, Southside Hospital, Bay Shore, New York.

Dr Cushner is a speaker and consultant for sanofi–aventis, a Data Safety Monitoring Boards Consultant for Astellas Pharmaceuticals, Inc, and on the Steering Committee for Bayer.

Dr Nett has no relevant financial relationships to disclose.

Correspondence should be addressed to: Fred D Cushner, MD, ISK Institute, 210 East 64th St, New York, NY 10065.

doi: 10.3928/01477447-20091103-50