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December 01, 2009
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The ACCP Guidelines for Thromboprophylaxis in Total Hip and Knee Arthroplasty

Abstract

The 1986 National Institutes of Health consensus conference Prevention of Venous Thrombosis and Pulmonary Embolism emphasized the high rates of venous thromboembolic disease (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), associated with orthopedic surgery of the lower extremity when performed without thromboprophylaxis. Total joint arthroplasty patients treated with placebo or as controls have, based on studies conducted between 1908 and 2002, a total DVT prevalence of 41% to 85% and a proximal DVT prevalence of 5% to 36% when examined by venography at 7 to 14 days. Prevalence of PE is less certain, but clinical studies have reported a range of 0.9% to 28% for all PE and 0.1% to 2% for fatal PE in control or placebo patients. As the number of total joint arthroplasties in the United States has grown—nearing 1,000,000 annually and expected to increase significantly over the next 20 years as the population ages—so too has interest in appropriate thromboprophylaxis. Methods of preventing VTE are either pharmacologic or mechanical. Guidelines from the American College of Chest Physicians make evidence-based recommendations for both pharmacologic and nonpharmacologic prophylaxis in the settings of total hip and total knee arthroplasty. These recommendations and their underlying rationale are discussed herein.

The argument for thromboprophylaxis in the settings of total hip and total knee arthroplasty (THA and TKA, respectively) reflects the risk for deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing these procedures.1,2 When examined by venography at 7 to 14 days, THA patients treated with placebo or as controls have a total DVT prevalence of 42% to 57%. Prevalence of proximal DVT ranges from 18% to 36%,2 and it is proximal clots that are more likely to produce symptoms or result in PE. Prevalence of PE is less certain, but clinical studies have reported a range of 0.9% to 28% for all PE and 0.1% to 2% for fatal PE.2 In studies using routine ventilation-perfusion lung scanning, 7% to 11% of patients have high probability scans at 7 to 14 days postoperatively.3,4 Venography studies without prolonged out-of-hospital prophylaxis indicate that new evidence of DVT develops in 20% to 25% of patients within 4 to 5 weeks of hospital discharge, and about 6% of these patients develop an intermediate or high probability lung scan.4 In the setting of TKA, the incidence of DVT without any prophylaxis ranges from 41% to 85%, of proximal DVT from 5% to 22%, of all PE from 1.5% to 10%, and of fatal PE from 0.1% to 1.7%.2

These incidence ranges are best considered in conjunction with procedural incidence. Although there is no single, centralized database in the United States that tracks statistics on joint replacement, whether numbers, types, or associated adverse outcomes, estimates regarding annual incidence can be made based on data from the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality (AHRQ)5 or Medicare.

According to the AHRQ, in 2003 approximately 200,000 THAs, 100,000 partial hip replacements, and 36,000 revisions were performed in the United States.6 The AHRQ recorded 383,500 hip replacements (based on all listed procedures) in 2005.7 In 2007, the AHRQ reported 555,800 knee arthroplasties (again based on all listed procedures) for 2005.5 Thus, it is reasonable to assume, given these figures (and prior rates of growth reported by AHRQ), that approximately 1,000,000 procedures related to hip or knee arthroplasty are performed annually in the United States. A 0.5% incidence of fatal PE in THA and TKA, for example, represents 5000 deaths.

It is not simply PE that thromboprophylaxis is intended to prevent, however. Nonfatal symptomatic or clinically silent DVT predisposes patients to development of post-thrombotic syndrome (PTS),8-12 which is associated with reduced quality of life and substantial health care expenditures.13-15 Among survivors of acute PE, chronic pulmonary hypertension is a serious complication that now appears to occur more frequently than once thought.16

DVT as an Endpoint

Clinicians can have widely divergent views as to what constitutes an appropriate endpoint for assessing the efficacy of a thromboprophylactic strategy. One argument is that the only useful endpoint is reduction in all-cause mortality or the incidence of fatal PE. Although these endpoints have the advantage of being (at least potentially) objectively definable, proving that a given strategy decreases all-cause mortality or the incidence of fatal PE is problematic. Choosing mortality as the endpoint effectively dismisses the significance of the acute and chronic burdens on the health care system imposed by nonfatal VTE. Choosing PE (fatal or otherwise) as the endpoint would require studies of impractical size. (The daunting mathematics of designing clinical trials to demonstrate an effect of thromboprophylaxis on incidence of PE are reviewed by the American College of Orthopaedic Surgeons in its recent guidelines.17) Moreover, obtaining autopsy confirmation of PE as cause of death is increasingly difficult.

For these reasons, most studies of VTE and its prevention have used composite endpoints including both symptomatic and asymptomatic DVT, the latter identified by diagnostic tests such as venography or duplex ultrasonography. Proximal DVT gives rise to PE, and 10% to 20% of distal DVTs propagate to the proximal veins,18-20 particularly in patients having major surgery of the hip.21 However, in studies of TKA, the majority of diagnosed DVT involved the calf and remained unchanged without any adverse outcomes.22-24 Thus, even though DVT is not a perfect endpoint, it is one that has reasonable value in predicting both acute and chronic adverse sequelae and it is an endpoint that permits trials enrolling manageable numbers of patients.25 Most important, randomized clinical trials conducted over the past 30 years—trials in which most events measured have been asymptomatic and symptomatic DVT—provide abundant evidence that primary thromboprophylaxis reduces the incidence of fatal PE.2,26,27 The National Quality Forum (NQF) released 6 measures in 2008 that “[target] the most common preventable cause of hospital death-venous thromboembolism.”28

ACCP Guidelines for Thromboprophylaxis During Hip and Knee Arthroplasty

The first consensus conference on thromboprophylaxis was held at the National Institutes of Health in 1986.29 The conference participants recognized that patients undergoing various types of surgery, particularly major orthopedic surgery, are at high risk for development of DVT and PE, and they made a series of recommendations regarding thromboprophylaxis. In retrospect, it is clear that the participants were hampered both by the quality of data and by the relatively few pharmacologic options available to them.

Since this initial effort, the conference process has been taken over by the American College of Chest Physicians (ACCP), which in June 2008 published the 8th edition of its recommendations. With publication of the 7th edition in 2004, the conference dropped the word “consensus” from the title to emphasize that, to the greatest extent possible, recommendations were evidence-based rather than “eminence-based.”30 The process whereby these guidelines are developed is well defined.31 Critical to the process is a grading system with 2 components: the score reflects both the strength of a recommendation and the conference participants’ level of confidence in the estimate of benefits and risks.

In terms of the former component, a strong grade 1 recommendation means that benefits clearly do or do not outweigh risks, burdens, and costs. A grade 2 recommendation means that there is less certainty regarding this balance. The latter component of the grading system is intended to indicate whether evidence upon which the recommendation is based is of high, moderate, or low quality (Table 1).32 In practice, a strong grade 1 recommendation could be based on evidence of moderate or low quality, whereas a weaker, grade 2 recommendation on evidence of high quality.

Table 1:Strength of Evidence in ACCP Guidelines for Thromboprophylaxis

The ACCP Recommendations

Pharmacologic Prophylaxis

Recommendations from the ACCP concerning pharmacologic prophylaxis for THA and TKA are summarized in Table 2. Four anticoagulants—warfarin, enoxaparin, dalteparin, and fondaparinux—are given 1A recommendations. Sites of action of these agents in the coagulation cascade are indicated in the Figure. For both THA and TKA, thromboprophylaxis is recommended for at least 10 days, and for THA for up to 35 days (in each case grade 1A recommendations). Use of aspirin or low-dose unfractionated heparin alone for VTE prophylaxis is not recommended (grade 1A) for any major lower extremity surgery.

Table 2: ACCP Grade 1A Pharmacologic Prophylaxis for THA and TKA

Figure: Simplified model of the coagulation cascade

Figure: Simplified model of the coagulation cascade and sites of action of anticoagulant drugs. The end result of the coagulation cascade is the conversion of fibrinogen to fibrin by factor IIa (thrombin), which is generated by the action of activated factor X (factor Xa) on prothrombin. Working through antithrombin, heparins (both unfractionated and low-molecular-weight) inactivate both activated factors X and II, although LMWHs have a relatively greater anti-factor Xa effect. Fondaparinux, also acting through antithrombin, inactivates factor Xa (but not factor IIa) while dermatan sulfate, acting through heparin cofactor II, inactivates factor IIa (thrombin). Warfarin inhibits synthesis of factors X and II as well as the other vitamin K-dependent factors, VII and IX. Direct factor Xa and thrombin inhibitors directly inactivate factors Xa and IIa (thrombin), respectively.

Oral anticoagulation with adjusted-dose warfarin sodium is the most common prophylaxis protocol used by orthopedic surgeons in North America. Adjusted-dose warfarin has the potential advantage of facilitating prolonged prophylaxis after hospital discharge as long as the appropriate infrastructure is available for monitoring the international normalized ratio (INR). Oral anticoagulation should be administered in a dose sufficient to prolong the INR to a target of 2.5 (range, 2-3). The initial oral anticoagulant dose is administered either before surgery or as soon after surgery as possible. However, even with early initiation of oral anticoagulation, the INR does not usually reach the target range until the third postoperative day. In an analysis by Geerts et al of 12 studies involving 1828 patients undergoing THA,33 use of warfarin was associated with a 22% risk of all VTE and a 5% risk of proximal DVT. A meta-analysis by Freedman et al yielded comparable results (Table 3, page 71).34 In an analysis of 949 TKA patients in 3 studies, the incidence of DVT was 45%, of asymptomatic PE 8.2%, and of symptomatic PE 0.4%.35

Table 3: Rates of Pulmonary Embolism and Deep Vein Thrombosis

The safety of warfarin prophylaxis depends on patients understanding the benefits and the risks of this medication. Clinical studies report major bleeding in 2.6% of patients, a rate similar to that observed with placebo (Table 4). Many exogenous and endogenous factors affect the level of anticoagulation achieved with a given dose of warfarin, including other medications, smoking, alcohol, foods, changes in the level of physical activity, and cytochrome P450 2C9 polymorphisms and the factor IX propeptide mutation. Patients must be aware of these interactions and monitor themselves for any symptoms of over-anticoagulation. Optimal use of warfarin requires consideration of the time course of its effects, close monitoring of the INR, patient education, and a systematic approach.

Table 4: Rates of Major and Minor Bleeding by Type of Thromboprophylaxis

In 1993, low-molecular-weight heparins (LMWHs) were approved for prophylactic use for THA, and they have been adopted in practice by many clinicians. The most commonly used LMWHs in North America are enoxaparin given subcutaneously at a dose of 30 mg every 12 hours starting 12 to 24 hours after surgery and dalteparin, also given subcutaneously, starting 4 to 6 hours after surgery at a dose of 2500 IU and then continued once daily at a dose of 5000 IU (Table 2). LMWHs have been studied extensively and are highly effective and generally safe. Geerts et al looked at 30 studies of LMWH prophylaxis in 6246 patients undergoing THA.33 Prevalence of all DVT was 16% (relative risk reduction [RRR], 70%) and of proximal DVT 6% (RRR, 78%). The rate of PE was 0.4%. These data are comparable to those obtained by Freedman et al (Table 3).34

Low-molecular-weight heparins are pharmacologically different from unfractionated heparin (UFH). The LMWHs bind less to plasma proteins and endothelial cells, resulting in (1) a more predictable dose-response, (2) a dose-independent mechanism of clearance, and (3) a longer plasma half-life, allowing once- or twice-daily dosing. Unlike UFH, which by definition has anti-factor Xa–to–anti-factor IIa ratio of 1:1, LMWHs have relatively greater ability to target factor Xa, with anti-factor Xa–to–anti-factor IIa ratios ranging from 2:1 to 4:1. They are associated with a lower incidence of heparin-induced thrombocytopenia than UFH, but like UFH, their anticoagulant effect can be (at least partially) reversed with protamine sulfate.

Bleeding remains a concern with LMWH prophylaxis. One trial has shown an increase in bleeding complications.36 Another trial reported greater blood loss.37 However, in a meta-analysis, the incidence of major bleeding in 5412 patients receiving prophylaxis with enoxaparin was 2.2%, not significantly different from that observed with placebo (Table 4).34

Fondaparinux is a synthetic pentasaccharide that, like UFH and the LMWHs, exerts its effect through antithrombin (Figure). However, unlike UFH and the LMWHs, the size of the fondaparinux molecule (and the resulting geometry of its interaction with antithrombin) means that it only has an inhibitory effect on factor Xa. Fondaparinux has been shown to provide effective prophylaxis in a once-daily subcutaneous fixed dose of 2.5 mg in THA, TKA, and hip fracture surgery (Table 2). Its elimination half-life is 17 to 21 hours, and because it is entirely renally cleared, its use is contraindicated in patients with severe renal insufficiency (estimated glomerular filtration rate <30 mL/min). There is no reversal agent for fondaparinux.

In a meta-analysis of 4, phase 3 trials comparing fondaparinux to enoxaparin in major orthopedic surgery (2 trials in THA, 1 in TKA, and 1 in hip fracture), the total incidence of VTE was 6.8% (odds reduction over LMWH, 55%), with a 1.3% incidence of proximal DVT, a 0.3 incidence of symptomatic PE, and a 0.1% incidence of fatal PE. The reported rate of symptomatic VTE was 0.3%. Major bleeding was reported at a rate of 0.3% (Table 4).38

Comparing Agents for Pharmacologic Prophylaxis

In the ACCP guidelines, Geerts et al2 pooled the results of 5 trials (N=2979) that directly compared prophylaxis with LMWH and adjusted-dose warfarin or acenocoumarol in THA patients. The total incidence of DVT (proximal plus distal) was 20.7% in vitamin K antagonist (VKA)-treated patients and 13.7% in LMWH-treated patients (P=.0002), whereas the incidences of proximal DVT were 4.8% and 3.4%, respectively (P=.08). Major bleeding, however, occurred in 5.3% of LMWH-treated patients compared with 3.3% of VKA-treated patients (P=.002). This analysis was consistent with results of prior meta-analyses, which showed that LMWHs were significantly more effective than VKAs in preventing venographically detected DVT and proximal DVT, and were associated with a comparable or slightly greater risk for major bleeding.39,40 Although fondaparinux has not been compared with warfarin in head-to-head clinical trials in THA, in a trial comparing it with the North American regimen of enoxaparin (30 mg subcutaneously twice daily), it was as effective as enoxaparin in preventing VTE but was associated with a trend toward increased bleeding.41

Numerous trials have demonstrated that enoxaparin is more effective than warfarin for thromboprophylaxis in the setting of TKA.2 Fondaparinux has been shown to be significantly more effective than the North American enoxaparin regimen in preventing venographically defined DVT in the setting of TKA, but was associated with a significant increase in the rate of major bleeding.42

An increase in surgical site bleeding and in wound hematoma formation is noted with both LMWHs and fondaparinux, but the incidence of major bleeding with either is similar to that observed previously with placebo. The more rapid onset of anticoagulation with LMWHs and fondaparinux compared with warfarin accounts for the lower incidence of bleeding that has been described with warfarin. The choice of LMWH, fondaparinux, or warfarin for prophylaxis should reflect consideration of cost, convenience, availability of an infrastructure to provide safe oral anticoagulation, potential bleeding and thrombosis risks, and the planned duration of prophylaxis. Such selection is thus best made at the level of the specific hospital or, on occasion, at the level of the individual patient.

Nonpharmacologic Prophylaxis

Compression

The ACCP does not recommend nonpharmacologic prophylaxis with graduated compression stockings, intermittent pneumatic compression (IPC), or venous foot pumps (VFP) for patients undergoing THA who are not at high risk for bleeding. However, for those who are at high risk for bleeding, “optimal” use of IPC or VFP is recommended for initial thromboprophylaxis. At such time as the bleeding risk decreases, pharmacologic prophylaxis should be instituted. In the setting of TKA, the ACCP considers optimal use of compression to be an alternative to pharmacologic prophylaxis. Optimal use of these devices requires proper fit and reflects the percentage of time used each day. A recently developed mobile compression device that can be worn when out of bed either in the hospital or at home has been reported to have a compliance rate of 77.7% to 87.1%.43-45

The ACCP makes no recommendations concerning multimodal therapy because data from prospective trials comparing multimodal with single modalities are unavailable.

Prophylaxis Duration

Historically, prophylaxis in the setting of TJR was continued for the entire duration of a 7- to 14-day hospitalization, but with the length of hospital stays now being 5 days or fewer, the period of in-hospital prophylaxis may be inadequate. Some studies suggest that the risk for DVT may persist for as long as 2 months after THA.46-48 A study in which warfarin prophylaxis was continued for 4 weeks after hospital discharge reported a 5.1% prevalence of symptomatic, confirmed DVT in the nontreated group and a 0.5% prevalence in the warfarin-treated group.49 In an analysis of 6 placebo- controlled trials in THA evaluating extended prophylaxis with LMWH, the prevalence of DVT in the placebo group was 22.5% and in the LMWH group was 7.9% (RR, 41%), whereas that of proximal DVT was 11.2% and 3%, respectively (RR, 31%).50 Extended prophylaxis for up to 35 days following THA with enoxaparin is superior to conventional prophylaxis for 7 to 10 days, with a 65% reduction in the relative risk for VTE.51

Cost-effectiveness

Defining relative cost-effectiveness of different approaches to prophylaxis is challenging because of changing costs of prophylaxis agents, the need for (and associated costs of) monitoring when oral anticoagulation is used, and increasing use of extended prophylaxis. In a pharmacoeconomic analysis comparing enoxaparin and warfarin for short-term orthopedic thromboprophylaxis, use of enoxaparin yielded a very small increment in quality-adjusted life-years relative to warfarin at a net cost of $133/patient. However, when costs associated with long-term complications of VTE, including PTS, recurrent VTE, and mortality, were considered in the analysis, enoxaparin proved cost-saving.52

Conclusion

Risks accompany any major surgical procedure such as THA or TKA. VTE and its sequelae have been identified as a significant surgical risk. Evidence-based guidelines are available to the surgeon who has the opportunity and responsibility to choose a protocol that has the best risk-benefit ratio for any given patient. VTE prophylaxis in THA and TKA is a changing field with new agents and devices becoming available. Physicians should stay current and be willing to adopt new protocols when evidence-based medicine demonstrates that a novel approach is associated with an improved risk-benefit ratio relative to existing strategies.

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Author

Dr Colwell is from the Shiley Center for Orthopaedic Research and Education at Scripps Clinic, La Jolla, California.

Dr Colwell is a consultant for Stryker.

Correspondence should be addressed to: Clifford W. Colwell Jr, MD, 11025 N Torrey Pines Rd, Ste 140, La Jolla, CA 92037.

doi: 10.3928/01477447-20091103-51