Benefits of Novel Oral Anticoagulant Agents for Thromboprophylaxis after Total Hip or Knee Arthroplasty

Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are among the most common orthopedic procedures performed in the United States, with almost 300,000 THA surgeries and more than 500,000 TKA surgeries performed annually.¹ This number is projected to rise to approximately 572,000 annual THA surgeries and 3.5 million annual TKA surgeries by 2030.¹ THA and TKA procedures improve mobility and quality of life, but patients undergoing these surgeries are at a significantly increased risk for developing postoperative venous thromboembolism (VTE).^2-4 VTE comprises both deep-vein thrombosis (DVT) and pulmonary embolism (PE). In the absence of thromboprophylaxis, proximal DVT occurs in approximately 5% to 36% of patients who have THA and TKA.⁵ PE occurs in 50% of patients with proximal DVT,⁴ and proves fatal in approximately 15% of these patients.⁶

VTE is also associated with significant long-term complications, such as postthrombotic syndrome, chronic thromboembolic pulmonary hypertension, and an increased risk of recurrent events.⁷ Postthrombotic syndrome develops in 23% to 60% of patients, often in the 2 years after a DVT, and approximately 10% of cases are considered to be severe.⁸ Approximately 4% of patients with PE are diagnosed with chronic thromboembolic pulmonary hypertension within 2 years⁹; approximately 10% of patients who experience VTE after THA or TKA are readmitted to the hospital within 3 months after discharge.¹⁰ The incidence of VTE can be effectively reduced with the use of thromboprophylactics, including vitamin K antagonists, low-molecular-weight heparins (LMWHs), or fondaparinux (Arixtra). Thromboprophylaxis reduces the cumulative incidence of symptomatic VTE to 1.7% within 3 months of THA and to 2.3% within 3 months of TKA.¹¹ However, these agents pose a number of management challenges that limit their use and increase the clinical and economic burden on patients, caregivers, and healthcare resources.

Effective prophylaxis may also be complicated by poor adherence to guideline recommendations, possibly resulting from physicians’ concern about the risk for bleeding or the difficulties of maintaining prophylaxis in an outpatient setting. Newly developed oral anticoagulants have the potential to address many of the limitations associated with vitamin K antagonists, LMWHs, and fondaparinux. They may also simplify treatment strategies for these patients, encourage compliance with therapy, and reduce the economic burden of VTE.

The Economic Burden of VTE

The costs of managing acute and chronic VTE are considerable, particularly those associated with hospitalization, long-term therapy, and monitoring.^12,13 In the United States, management of VTE costs almost $500 million annually.¹³ A study using data from a large healthcare claims database showed that for patients with in-hospital VTE, mean billed charges were $18,834 higher than for matched controls (ie, individuals of the same age who underwent the same procedure but had no claim for DVT or PE); the increment was $7351 in TKA patients and $27,034 in THA patients.¹⁰ Another analysis of the economic burden of VTE in hospitalized patients estimated the cost of managing an initial episode of DVT to be between $7712 and $10,804, and between $9566 and $16,644 for an initial PE event.¹⁴

Long-term complications of VTE, such as recurrent VTE, postthrombotic syndrome, and chronic thromboembolic pulmonary hypertension, add to the cost of treatment.^15-17 The cost of hospital readmission for a recurrent DVT is estimated to be 21% greater than the cost for the initial DVT event, mainly because of the longer hospital stay.¹⁶ The long-term costs of treating postthrombotic syndrome are estimated to add 75% to the cost of treating the initial DVT.¹⁷ The considerable morbidity associated with chronic thromboembolic pulmonary hypertension also adds to costs. The direct cost of managing patients with chronic thromboembolic pulmonary hypertension has been estimated to be $4782 per patient per month (PPPM) versus $511 PPPM for controls, with circulatoryrespiratory– related costs accounting for 55% of the excess costs.¹⁸

Although thromboprophylaxis reduces the incidence of VTE and its associated costs, the costs associated with anticoagulation need to be considered, including those for drug acquisition, administration, and routine coagulation monitoring. In addition, because the use of anticoagulants may increase the risk for bleeding, the cost of bleeding management should be taken into consideration. A recent analysis of insurance healthcare claims found that the monthly incremental costs per patient are similar for the management of VTE and bleeding events ($2729 and $2696, respectively) in patients with major orthopedic surgery.¹⁹ However, the overall 3-month risk for bleeding was substantially lower than the risk for VTE.¹⁹

Barriers to Optimal Thromboprophylaxis

Although thromboprophylaxis can effectively reduce the incidence of VTE in patients undergoing THA or TKA, barriers to optimal thromboprophylaxis exist.

These barriers include:

• Poor implementation of guidelines
• Bleeding concerns
• Limitations of existing agents.

Poor Implementation of Guidelines for the Prevention of VTE

Clinical practice guidelines for the prevention of VTE have been published by the American College of Chest Physicians (ACCP) every 3 years for more than 20 years.^3,20 The most up-to-date version of these guidelines recommends the routine use of traditional anticoagulants— LMWHs, fondaparinux, vitamin K antagonists (ie, warfarin)—aspirin, or one of the new oral anticoagulants—rivaroxaban (Xarelto), dabigatran (Pradaxa), or apixaban (Eliquis)—for pharmacologic thromboprophylaxis in individuals who have undergone THA or TKA surgery.³ The American Academy of Orthopaedic Surgeons (AAOS) recently published updated guidelines for the prevention of VTE in patients undergoing THA or TKA.²¹ The AAOS recommends the use of mechanical compression devices in appropriate patients, in addition to pharmacologic agents.²¹

Retrospective analyses of data collected by the Global Orthopaedic Registry (GLORY) between June 2001 and December 2004 have demonstrated limited adherence to guidelines for VTE prophylaxis in the United States, with room for much improvement.^22,23 One barrier to the implementation of guidelines in the United States may be the considerably shorter period of time that patients undergoing THA or TKA spend in the hospital compared with other countries. In the United States, median lengths of hospital stay are only 3 and 4 days for THA or TKA, respectively, and it is likely that the duration of prophylaxis recommended by the ACCP (10-35 days) is difficult to achieve in an outpatient setting.^3,22 A retrospective cohort study has also showed that physicians often use lower-than-recommended doses of LMWH, inadequate bridging protocols when switching from injectable agents to warfarin (which takes 3-5 days to reach effective levels), and insufficient or no therapy after hospital discharge.²⁴

Concerns about Bleeding

Although the major complication of all anticoagulant therapy is bleeding, when thromboprophylaxis is administered postsurgically to patients undergoing THA or TKA, the rates of major bleeding events are low. Major bleeding with LMWH prophylaxis after THA or TKA is estimated to be between 3% and 5%.²⁵ Major bleeding with warfarin use is also low (approximately 4% at a target international normalized ratio of 2.0) and is heavily dependent on the patient’s predisposing risk factors, such as comorbid conditions (eg, cancer, hypertension, heart disease, cerebrovascular disease, renal insufficiency, and paraplegia).²⁵ Patient characteristics (eg, age and a history of bleeding), concomitant medications, and incorrect timing and/or dosing of the anticoagulant also contribute to bleeding risk.²⁵ For example, a patient aged >75 years who weighs <50 kg and has compromised renal function is at an increased risk for a major bleeding event. Complications may be avoided by taking a highly conservative approach to anticoagulation in these individuals; therefore, the risk for bleeding with appropriate use of thromboprophylactics may be overestimated.^26,27

Limitations of Current Agents

Existing anticoagulants carry a number of limitations that contribute to suboptimal thromboprophylaxis in patients undergoing THA or TKA. LMWHs and fondaparinux are inconvenient, particularly in the outpatient setting, because they are administered parenterally, and their use may accrue significant costs related to home administration by nurses, patient training, and monitoring. In addition, all heparins, including LMWHs, carry the risk for heparin-induced thrombocytopenia, and long-term therapy is associated with osteoporosis.²⁸ Orally administered warfarin has complex pharmacokinetic and pharmacodynamic properties and a narrow therapeutic window, making routine coagulation monitoring and dose adjustments essential.^28,29 Warfarin also has a slow onset and offset of action, which means that patients already receiving warfarin may need to adhere to complicated perioperative bridging protocols. In addition, warfarin has multiple food and drug interactions, and its metabolism is susceptible to numerous genetic polymorphisms.^28,29

The New Oral Anticoagulants

Table

Three new oral anticoagulants have undergone phase 3 clinical studies in patients undergoing THA or TKA in the United States (Table).^30-40 Two of these agents— rivaroxaban and apixaban—are factor Xa inhibitors, whereas dabigatran is a direct thrombin inhibitor. The beneficial characteristics of these 3 new anticoagulants include⁴¹:

• Fixed dosing as a result of their predictable pharmacokinetics
• No requirement for coagulation monitoring
• Few drug–drug and drug–food interactions
• Once- or twice-daily oral administration.

Rivaroxaban

Rivaroxaban selectively blocks the active site of factor Xa and does not require a cofactor (such as antithrombin) for activity. Because rivaroxaban has predictable pharmacokinetic and pharmacodynamic properties and a low potential for interactions with food or other drugs, it can be administered as a fixed dose, without the requirement for routine coagulation monitoring.⁴² A large phase 3 investigative program composed of 4 clinical trials that compared rivaroxaban with enoxaparin (Lovenox) in patients undergoing THA or TKA— Regulation of Coagulation in Orthopaedic Surgery to Prevent Deep Vein Thrombosis and Pulmonary Embolism (RECORD)—has been completed.⁴² The primary efficacy end point of the 4 RECORD studies was total VTE—the composite of any DVT, nonfatal PE, and all-cause mortality (Table).^30-33

The RECORD1 trial demonstrated that rivaroxaban 10 mg once daily was superior to enoxaparin 40 mg once daily for 30 to 35 days after THA,³⁰ whereas the RECORD2 study demonstrated the superiority of longterm thromboprophylaxis with rivaroxaban 10 mg once daily (31-39 days) versus short-term thromboprophylaxis with enoxaparin 40 mg once daily (10-14 days) in patients undergoing THA.³¹ The RECORD3 and RECORD4 studies demonstrated the superior efficacy of rivaroxaban 10 mg once daily versus enoxaparin 40 mg once daily and 30 mg twice daily (a regimen approved in North America after TKA), respectively, for 10 to 14 days after TKA.^32,33 In a pooled analysis of the RECORD studies, rivaroxaban significantly reduced the composite of symptomatic VTE and all-cause mortality versus enoxaparin and was associated with a similar safety profile.⁴³

In July 2011, rivaroxaban became the first new oral agent to be approved by the US Food and Drug Administration (FDA) in the United States for prophylaxis of DVT (which may lead to PE) in patients undergoing THA or TKA, based on results from the RECORD1, 2, and 3 trials. The Centers for Medicare & Medicaid Services has issued a memo that rivaroxaban administration after THA and TKA is Surgical Care Improvement Project–compliant as of July 2, 2011.

Apixaban

Another oral, direct factor Xa inhibitor, apixaban, has also been studied in phase 3 trials in patients undergoing THA or TKA (Table).^34-36 Apixaban is currently approved for the prevention of VTE after THA or TKA in the European Union. In the Apixaban Versus Enoxaparin for Thromboprophylaxis After Knee Replacement (ADVANCE)-1 trial, apixaban 2.5 mg twice daily was compared with enoxaparin 30 mg twice daily in patients post-TKA. However, apixaban did not meet the prespecified statistical criteria for noninferiority for the composite primary efficacy end point of asymptomatic and symptomatic DVT, nonfatal PE, and death from any cause during treatment.³⁴ In the ADVANCE-2 and ADVANCE-3 trials, apixaban 2.5 mg twice daily was compared with enoxaparin 40 mg once daily and demonstrated superior efficacy in patients who had undergone TKA (ADVANCE-2) and THA (ADVANCE-3).^35,36 Apixaban compared with enoxaparin was not associated with an increase in bleeding events in any of the 3 ADVANCE studies.^34-36

Dabigatran

Dabigatran etexilate is an oral direct thrombin inhibitor that has a low potential for drug–drug interactions and a predictable anticoagulant effect.⁴⁴ Dabigatran is approved for VTE prophylaxis after THA/TKA surgery in Canada and the European Union, but not currently in the United States. Dabigatran 150 mg or 220 mg once daily demonstrated noninferiority to enoxaparin 40 mg once daily for 28 to 35 days after THA in the RE-NOVATE and RENOVATE II studies, and for 6 to 10 days after TKA in the RE-MODEL study (Table).^37-39 In the RE-MOBILIZE study (TKA), dabigatran failed to meet the noninferiority criteria when compared with enoxaparin 30 mg twice daily.⁴⁰ Dabigatran had a similar safety profile versus enoxaparin in all 4 studies.^37-40

Limitations of the New Oral Anticoagulants

Despite their important advantages―oral administration, a rapid onset and offset of action, predictable pharmacokinetics that allow fixed dosing, no requirement for coagulation monitoring, and significantly fewer food–drug and drug–drug interactions than warfarin ―the new oral anticoagulants also have some limitations. Although to date rivaroxaban is the only anticoagulant approved in the United States for use in orthopedic patients, efficacy and safety data from phase 3 clinical trials facilitate assessment of the limitations of dabigatran and apixaban as well. Renal function is very important for dabigatran; 80% is renally excreted, with the remainder excreted via the bile.^44,45 There has been recent concern regarding excess bleeding in patients receiving dabigatran. These reports are currently being investigated by the FDA. The rivaroxaban dose must be adjusted in patients with renal insufficiency, and its use should be avoided in patients with severe renal impairment (creatinine clearance <30 mL/min).⁴² Dabigatran requires a dose adjustment if creatinine clearance is <30 mL/min.⁴⁵ Caution should be used when any of these agents is administered concomitantly with either a P-glycoprotein inhibitor or inducer, or a strong cytochrome P-450 3A4 inhibitor or inducer.^42,45,46 Rivaroxaban should be used with caution in patients receiving neuraxial anesthesia, because epidural or spinal hematomas have occurred in that setting.⁴²

Reversal

None of the new oral agents has a specific antidote that will completely reverse its anticoagulant effects. Data regarding the potential reversibility of these drugs are primarily derived from animal studies. Nevertheless, for patients who experience mild bleeding while taking these agents, discontinuation of therapy may be considered a reasonable strategy because of their relatively short half-lives. For patients who experience moderateto- severe bleeding, supportive measures include fluid replacement, hemodynamic support, and blood products, including fresh frozen plasma.^47,48 For those patients whose bleeding is considered life-threatening, prothrombin complex concentrate or recombinant activated factor VIIa (rVIIa) have been used with some success in healthy volunteers receiving dabigatran or rivaroxaban.⁴⁸ Administration of rVIIa significantly reduced bleeding times in rats receiving high doses of dabigatran in one study,⁴⁷ but did not reduce hematoma size in mice with dabigatran-induced intracranial hemorrhage in another study.⁴⁹

Cost and Cost-Effectiveness of the New Oral Anticoagulants

Because no routine coagulation monitoring is required with the new oral anticoagulants—unlike with warfarin—the costs associated with the administration and monitoring of these medications are eliminated. These costs were found to be $51.25 PPPM in a 2004 study,⁵⁰ which would be at least $10 more in 2012 dollars. Although enoxaparin has been shown to be more costeffective than warfarin,⁵¹ enoxaparin’s subcutaneous route of administration adds to its costs. In 2002, home nursing visits for outpatient administration of enoxaparin amounted to approximately $100 for 1 course of therapy.⁵² These additional costs are eliminated with the new oral anticoagulants.

Although pharmacoeconomic data are currently sparse for these new agents, the few pharmacoeconomic models that have been developed in this setting show these drugs to be more cost-effective than enoxaparin. In one study, it was found that for THA patients in the UK National Health Service, the use of dabigatran was associated with substantial cost-savings compared with enoxaparin, primarily because it was not necessary to train patients in the use of an injectable agent.⁵³ Avoidance of expenses associated with heparin-induced thrombocytopenia, needlestick injuries, and needle disposal also played an important role in reducing costs.⁵³

In cost-effectiveness analyses of the RECORD1 and RECORD2 trials of patients undergoing THA, rivaroxaban was found to be more cost-effective than enoxaparin, because of the lower costs of hospitalization and administration associated with rivaroxaban as a result of reduced rates of VTE.^54,55 Similar results were seen in RECORD3 in patients undergoing TKA; in this trial, the need for either home nurse time or training in selfadministration of the injectable agent enoxaparin resulted in higher costs.⁵⁶ In another study using data from RECORD1, 2, and 3, rivaroxaban was found to reduce total costs to payers in both populations of patients undergoing either THA or TKA compared with enoxaparin.⁵⁷

Conclusion

Over the past 20 years, the incidence of VTE in patients who undergo THA or TKA has decreased markedly. This decline is explained, in part, by the uptake of new prophylactic agents, such as enoxaparin and fondaparinux. However, other improvements in patient care (eg, shorter surgery times, quicker and more intense rehabilitation programs, and multimodal approaches to pain management) may also have contributed to better patient outcomes. A quick review of clinical trial data suggests that among patients who received enoxaparin after THA as part of a clinical trial, VTE rates fell from 12% in the late 1980s⁵⁸ to approximately 8% in the late 1990s,⁵⁹ approximately 4.6% in the first years of the new century,⁶⁰ and >4% in clinical trials of new oral anticoagulants.^30,36 Despite this improvement, thromboprophylaxis remains suboptimal for the reasons discussed in this article. It is encouraging that new oral anticoagulants have demonstrated superior efficacy versus enoxaparin, while exhibiting safety profiles similar to established agents, and the simplified management associated with these new agents should encourage compliance with published guidelines for VTE prophylaxis.

With the number of THA and TKA surgeries increasing, safe and effective thromboprophylaxis is essential to mitigate the morbidity and mortality associated with VTE. The limitations of current agents, such as LMWHs and warfarin, further suggest a need for new therapies that can improve patient outcomes and reduce the clinical and cost burden associated with TKA/THA. The new oral anticoagulants have the potential to reduce the incidence of VTE after THA and TKA. In addition, compared with established agents, the new oral anticoagulants may produce significant cost-savings through reduced rates of VTE, improved safety, and reduced administration and monitoring costs.

Acknowledgment

The author would like to acknowledge Richard Dobson, PhD, who provided editorial support.

Study Funding

This study was funded by Janssen Scientific Affairs, LLC.

Author Disclosure Statement

Dr Friedman is a Consultant to Janssen and Exactech, is on the Speaker’s Bureau of Janssen, and has received research grants from Tournier.

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