Extended Thromboprophylaxis after Hip or Knee Replacement

ABSTRACT

Early discharge from the hospital after total joint arthroplasty has increased the need for extended outpatient thromboprophylaxis. Multiple controlled clinical trials and several meta-analyses of these data have examined various agents in different regimens. These data indicate that extended prophylaxis with a low-molecular-weight heparin after knee or hip arthroplasty significantly reduces the number of venous thromboembolic episodes with no increases in major bleeding. The data also show that >98% of patients given long-term low-molecular-weight heparin prophylaxis remain free from symptomatic deep venous thrombosis and pulmonary embolism. Therefore, to minimize patient risk safely and cost-effectively, extended prophylaxis with low-molecular-weight heparin once-daily for 4 weeks after surgery should be considered for patients undergoing total joint arthroplasty.

Without thromboprophylaxis, 45%-57% of patients who have undergone total hip replacement (THR) and 40%-84% of patients who have had total knee replacement (TKR) experience deep venous thrombosis.¹ Up to 30% of patients who have had hip replacements and up to 7% of patients who have had knee replacements may experience pulmonary embolism.¹ Both deep venous thrombosis and pulmonary embolism are associated with significant morbidity; the postoperative mortality rate due to pulmonary embolism following THR can be as high as 3%-6%.²

For these reasons, prophylaxis has become an accepted strategy for preventing thromboembolic complications after joint replacement surgery. An antithrombotic agent, such as warfarin or a low-molecular-weight heparin, was typically administered through the 5- to 14-day period of hospitalization. However, lengths of stay are decreasing dramatically at most institutions. Patients who have undergone TKR are now released from the hospital after 3-4 days, and patients who have had THR are discharged 4-5 days after surgery. As hospital stays decrease, so too does the opportunity for appropriate prophylaxis.

This reduction in hospitalization invokes a significant risk for thromboembolism in the outpatient environment. Results of prospective clinical trials using objective venography indicate a 19%-39% incidence of deep venous thrombosis 3 weeks after THR in patients who have received conventional inpatient prophylaxis after surgery.^3,4 Venous thromboembolism is the most common cause of emergency rehospitalization after THR.⁵

The risk of pulmonary embolism continues throughout the postoperative period. In a survey of approximately 8000 patients who had received thromboprophylaxis during THR, the mortality rate from pulmonary embolism was 1.04%. More than 50% of these patients died during the second postoperative week, almost 75% during the third week, 8% during the fourth week, and 5% five weeks after surgery.⁶

A strategy of extended prophylaxis (ie, prophylactic therapy administered daily for several weeks after discharge) has evolved in response to the changing institutional environment. Increasing awareness of other thrombotic risks has also stimulated interest in extended outpatient prophylaxis. These risks include the possibility of persistent activation of coagulation in certain patients,⁷ the presence of deep venous thrombosis of uncertain clinical significance at discharge, and the risk of postthrombotic syndrome, which is a long-term complication that can compromise functional improvement.^8-10

This review will examine efficacy and safety data from multiple controlled clinical trials, explore pharmaco- economic analyses of extended thromboprophylaxis, and apply these findings to clinical recommendations. Because enoxaparin is the only low-molecular-weight heparin that is approved for extended prophylaxis after THR, we emphasize data emerging from an array of controlled clinical trials that focus on this indication.

Clinical Trials with Enoxaparin

Figure 1: Incidence of thromboembolic events detected on venography in 233 evaluable patients receiving extended prophylaxis with enoxaparin versus placebo. (Data from Bergqvist et al.4) Figure 2: Incidence of thromboembolic events detected on venography in 173 evaluable patients receiving extended prophylaxis with enoxaparin versus placebo following hip arthroplasty. (Data from Planes et al.3) Figure 3: Incidence of thromboembolic events detected on venography: enoxaparin versus placebo following hip or knee arthroplasty. (Data from Comp et al.11) Abbreviations: DVT=deep venous thrombosis and PE=pulmonary embolism.

Three prospective, randomized, double-blind, placebo-controlled studies—one trial conducted in North America and two trials in Europe—have evaluated the efficacy and safety of extended prophylaxis with enoxaparin in preventing deep venous thrombosis.^3,4,11 The three trials featured similar study designs, although specific dosage and duration varied slightly.

Bergqvist et al⁴ treated 262 patients undergoing THR with enoxaparin (40 mg per day subcutaneously) for 10-11 days (range, 6-12 days) of hospitalization. Upon discharge, 131 patients received 40 mg of enoxaparin subcutaneously once a day and 131 patients received daily subcutaneous injections of placebo. The protocol dictated that on day 21 (range, day 19-23) postdischarge, prophylaxis would be stopped and patients would undergo bilateral venography to screen for deep venous thrombosis. Patients treated with 21-day extended enoxaparin prophylaxis remained >98% free of symptomatic deep venous thrombosis.⁴ The rates (P<.001) of deep venous thrombosis and proximal deep venous thrombosis in patients who received prophylactic enoxaparin were significantly lower than the rates in patients who received placebo (Figure 1).⁴

Other investigators reported similar findings.³ One hundred seventy-nine patients undergoing THR received 40 mg of enoxaparin subcutaneously once-daily for 13-15 days of hospitalization. After bilateral venography was performed to detect patients with deep venous thrombosis, patients were discharged and randomly assigned to either extended prophylaxis with enoxaparin or placebo. Injections continued daily until the next venographic evaluation at day 21 (±2 days). The overall rate of deep venous thrombosis was significantly lower in patients who received enoxaparin than in patients given placebo (Figure 2).³ The rate of proximal deep venous thrombosis was comparable in the two groups.³

The North American trial involved 968 patients who underwent THR or TKR.¹¹ All patients received 30 mg of enoxaparin subcutaneously every 12 hours for the 7-10 days of hospitalization. After discharge, 873 patients were randomized to receive daily subcutaneous injections of either enoxaparin (40 mg) or placebo until the scheduled screening bilateral venogram at day 21±2 days. The results of this trial demonstrate a significantly lower (P<.001) overall deep venous thrombosis rate in the THR patients treated with enoxaparin (8%) than in patients who received placebo (23.2%); this translated to a relative risk reduction of 65.5% (Figure 3).¹¹ Also, rates of proximal and distal deep venous thrombosis were lower in the enoxaparin group (Figure 3).¹¹

A significant number of patients in the placebo group were rehospitalized for clinically symptomatic thromboembolic events, whereas >96% of patients given prolonged therapy with enoxaparin did not require rehospitalization for venous thromboembolism.¹¹ Long-term administration of enoxaparin in patients undergoing TKR did not confer a statistically significant increase in additional benefit in comparison with short-term enoxaparin therapy.¹¹ The incidence of hemorrhagic or other drug-related complications was similar between both treatment groups in the TKR and THR populations. The authors concluded that prolonging thromboprophylaxis with enoxaparin significantly reduced the prevalence of deep venous thrombosis in patients undergoing THR.¹¹

Meta-Analyses

Eikelboom et al¹² analyzed data from nine randomized trials that compared the use of extended prophylaxis with various low-molecular-weight heparins or unfractionated heparin versus placebo or untreated control in approximately 4000 patients undergoing THR or TKR (Table 1).^3,4,11,13-18 The clinical endpoints were symptomatic venous thromboembolism including deep venous thrombosis and pulmonary embolism, asymptomatic deep venous thrombosis by venography, major or minor bleeding, or any cause of mortality.

Table 2 demonstrates the significant impact of pharmacologic prophylaxis with low-molecular-weight heparins or unfractionated heparin on the overall rate of venographically demonstrated deep venous thrombosis. Prophylaxis decreased the rate of proximal deep venous thromboses by two-thirds and the rate of distal deep venous thrombosis by approximately 40%.¹² With the exception of one unfractionated heparin trial, the risk reduction favored long-term prophylaxis with low-molecular-weight heparin across each study (Figure 4).¹² The rate of risk reduction was higher in THR than in TKR.¹²

The decrease in asymptomatic venous thromboembolism correlated with a reduced number of symptomatic events. As shown in Table 3, extended prophylaxis significantly decreased symptomatic events occurring postdischarge, with >98% of all patients in the extended prophylaxis group free from symptomatic deep venous thrombosis and pulmonary embolism.¹² Thus, venographic deep venous thrombosis is a good surrogate marker for clinical episodes.

All of these benefits were achieved with no compromise in safety, as measured by episodes of major bleeding or mortality.¹² These collective data indicate that extended prophylaxis following knee or hip arthroplasty significantly reduces the number of venous thromboembolic episodes with no excesses in major bleeding. The data demonstrate that a decrease in the rate of asymptomatic venographic deep venous thrombosis translates into a decrease in the symptomatic deep venous thrombosis rate. The reduction in risk is approximately 20 symptomatic events per 1000 treated patients.¹²

A second meta-analysis of six of these studies supports these findings and, therefore, it can be concluded that extended prophylaxis with low-molecular-weight heparin results in a 50% odds reduction in the risk of developing venous thromboembolism after lower limb arthroplasty.¹⁹ In this analysis, the overall frequency of clinical venous thromboembolism was 1.6% after extended prophylaxis versus 3.3% in patients receiving placebo.¹⁹ These findings indicate that >98% of patients receiving long-term prophylaxis with low-molecular-weight heparin do not experience clinical symptoms of deep venous thrombosis and pulmonary embolism.

At this point, extended prophylaxis appears to be more effective in THR than in TKR. However, further studies in knee surgery are required.

Cost-Efficacy

The extent to which low-molecular-weight heparins such as enoxaparin can achieve widespread clinical acceptance is not solely an issue of clinical efficacy or safety. With managed care resting on a foundation of cost-efficiency, any agent used for extended thromboprophylaxis must not place significant burdens on the cost of care.

Enoxaparin has been comprehensively studied from a pharmacoeconomic as well as clinical perspective, and these studies are reviewed in detail elsewhere.²⁰ A French decision analysis model of data from enoxaparin clinical trials in extended thromboprophylaxis has shown that the outpatient administration of enoxaparin for 3 weeks to patients who have had THR is a cost-effective alternative to perioperative thromboprophylaxis when weighed directly against the costs of symptomatic thromboembolic events or death associated with thromboembolic events.²¹ A Swedish decision analysis model found the same results when enoxaparin was self-administered in the majority of patients.²² A decision tree model that also included lifelong outcomes and indirect costs of care demonstrated that 28 days of extended thromboprophylaxis with enoxaparin cost less and increased life expectancy more than a similar duration of unfractionated heparin prophylaxis.²³

Another study was conducted to compare the cost of extended prophylaxis with enoxaparin versus warfarin in a decision tree analysis of this strategy in patients undergoing THA.²⁴ Warfarin therapy was classified as minimal, moderate, or maximal, depending on the intensity of prothrombin determinations. The cost of prophylaxis with enoxaparin was then compared with each of these intensities of warfarin therapy and found that the cost of administering enoxaparin exceeded that of administering warfarin after approximately 3 weeks. In patients who required maximal monitoring of warfarin, enoxaparin could be given for 31 days before its total costs exceeded those of warfarin (Table 4).²⁴ The critical factors that enhanced the cost-effectiveness of enoxaparin related directly to the expense of monitoring patients receiving warfarin and the cost of complications and treatment failures in those patients. Therefore, although the acquisition cost of enoxaparin was typically higher than that of warfarin, the total cost associated with administration of the low-molecular-weight heparin remained below that of warfarin because of the need for ongoing monitoring.²⁴

Figure 4: Risk of asymptomatic venous thromboembolism in a meta-analysis of heparin studies. (Adapted from Eikelboom JW, et al.12 Copyright 2001, with permission from Elsevier Science.)

Risk Stratification

The primary goal of risk stratification is to aid the surgeon in deciding which patients require extended prophylaxis after hospital discharge. A checklist can be used to rate each patient based on points assigned to a variety of risk factors that occur within 24 hours of surgery.²⁵ The system allows the surgeon an opportunity to rate the need for extended prophylaxis based on the patient’s risk factors.

Postthrombotic Syndrome

Extended prophylaxis should also be considered to reduce the risk of postthrombotic syndrome, which can be a long-term complication of total joint arthroplasty.

Many surgeons do not recognize that this is a significant clinical concern among their patients, possibly because long-term (.10 years) clinical follow-up focuses on evaluation of the joint for symptomatic or radiographic failure, rather than a broader assessment for vascular conditions. Patients who develop complications are more likely to consult their internist and be referred to a vascular surgeon, rather than an orthopedic surgeon.

However, in clinical studies that specifically look for postthrombotic syndrome as a complication, data indicate that 24% of patients develop postthrombotic syndrome or postphlebitic syndrome within 3 years of hip or knee arthroplasty, with a much higher ratio of proximal to distal events.^8-10 Therefore, although clinically evident venous thromboembolism may be a legitimate endpoint for measuring failure of prophylaxis after total knee or hip arthroplasty, postthrombotic syndrome may be a more legitimate endpoint for long-term surgical follow-up.

Recommendations

Given current knowledge and surgeons’ desire to safely minimize patient risk at a reasonable cost, it is sensible to consider extended prophylaxis with an antithrombotic agent for 4 weeks after surgery.

Patients undergoing THR may receive either warfarin (7.5 mg or 10 mg) the night before surgery followed by a daily dose to maintain an international normalized ratio of 2-3, or postoperative enoxaparin (30 mg subcutaneously every 12 hours) starting 12-24 hours after the procedure. Alternatively, prophylaxis with enoxaparin (40 mg daily) can be initiated preoperatively. Inhospital mechanical prophylaxis can be added to these pharmacologic measures. Extended prophylaxis with enoxaparin (40 mg daily) should be considered in patients undergoing THR because the majority of patients have multiple risk factors.

In TKR, enoxaparin (30 mg subcutaneously every 12 hours) can be initiated the morning after surgery and continued for a minimum of 5-7 days. Extended prophylaxis should be considered for patients at increased risk (ie, patients who have preexisting venous or arterial thromboembolic disease, patients who are slow to ambulate, elderly or obese patients, and patients who have a history of cancer). Unless otherwise contraindicated, all patients undergoing hip or knee arthroplasty should be advised to take one baby aspirin daily for prevention of stroke, myocardial infarction, and other arterial complications.

Conclusion

Lower extremity total joint arthroplasty is associated with a high risk of postoperative venous thromboembolism. Traditionally, antithrombotic prophylaxis has been administered during hospitalization, typically for 5-14 days. Currently, patients are spending less time in the hospital after surgery. Therefore, they must continue thromboprophylaxis after hospital discharge.

Data from clinical studies suggest that there is a protracted risk of thromboembolic disease that extends many weeks following the procedure. Extended thromboprophylaxis has been shown in multiple clinical trials to be a safe and effective strategy for reducing the risk of venous thromboembolism after joint replacement. Of the therapeutic options (eg, low-molecular-weight heparins, unfractionated heparin, or warfarin), only enoxaparin is approved for use in extended prophylaxis following THR. Data from controlled trials provide evidence supporting the notion that prolonging thromboprophylaxis with enoxaparin significantly reduces the prevalence of deep venous thrombosis. This conclusion is supported by several pharmacoeconomic analyses that confirm the cost-efficacy of extended enoxaparin prophylaxis when compared with the total cost of a thromboembolic event or compared with extended prophylaxis with agents that require extensive laboratory monitoring, such as warfarin or unfractionated heparin.

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Authors

From Charleston Orthopaedic Associates, Charleston, SC.