Prevention of Venous Thromboembolism After Total Joint Replacement: Rivaroxaban Update

The number of total hip and knee replacement surgeries is increasing, and consequently, more patients are at risk of venous thromboembolism (VTE).¹ Without thromboprophylaxis, the incidence of proximal deep vein thrombosis (DVT) is about 18% to 36% following total hip replacement (THR) and about 5% to 22% following total knee replacement (TKR). The incidence of total pulmonary embolism (PE) has been estimated at 0.9% to 28% in THR and 1.5% to 10% in TKR, and the incidence of fatal PE has been estimated to be as high as 2% following total joint replacement surgery.2 Despite the availability of effective anticoagulant agents for thromboprophylaxis, symptomatic VTE continues to occur in 1.3% to 10.0% of patients in the 3-month period following joint replacement surgery.²

VTE following THR or TKR represents a significant source of morbidity and mortality as well as a financial burden on the health care system. This burden is increased further by the complications of VTE—including a high rate of recurrence, postthrombotic syndrome (PTS), and pulmonary hypertension—which may be more debilitating than the primary event.^3-5 Effective prophylaxis of VTE is paramount in reducing the incidence of these consequences.

Rivaroxaban, a Factor Xa inhibitor, is a novel anticoagulant that has recently been approved by the U.S. Food and Drug Administration (FDA) for prophylaxis of DVT in patients undergoing THR or TKR as well as for reduction of the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AFib).⁶ Clinical trials have shown that rivaroxaban is superior to enoxaparin, the standard of care, in preventing VTE after total joint replacement, and cost-effectiveness studies have demonstrated that rivaroxaban may potentially be a cost-saving agent.

This clinical review will address the economic and public health burden of VTE following THR and TKR and evaluate the novel anticoagulants that have been studied for this indication, including rivaroxaban. The safety and efficacy of rivaroxaban will be discussed, along with cost-effectiveness issues and practical management information.

The Economic Burden of VTE
VTE is the most common cause of hospital readmission following THR.² The occurrence of VTE is reported to significantly increase the length of hospital stays and health care charges in patients undergoing TKR or THR. For example, one study reported health care charges for the index admission that were $9,297 higher for inpatients who experienced VTE compared with patients with TKR who did not have a VTE (P = .02).⁷ Similarly, for patients with THR, health care charges were $25,853 higher for inpatients who experienced VTE compared with patients who did not (P < .01).⁷

According to Spyropoulos and Lin, the total annual health care cost of a VTE (not limited to orthopedic patients) is $7,594 to $16,644, depending on the type of VTE (DVT or PE) and whether it was the primary or secondary diagnosis on discharge.⁸ These costs are significant, especially when multiplied by the number of THR and TKR surgeries performed in the U.S. Furthermore, VTE complications, such as PTS, represent an additional driver of health care expenditures.^5,9,10

VTE Prophylaxis Guidelines
Both the American College of Chest Physicians (ACCP) and the American Academy of Orthopaedic Surgeons (AAOS) have published evidence-based guidelines for the prevention of VTE following total joint replacement.^2,11 The 2012 version of the ACCP guidelines recommended the routine use of low-molecular-weight heparins (LMWHs), fondaparinux, low-dose unfractionated heparin, aspirin, adjusted-dose warfarin, rivaroxaban, apixaban, or dabigatran for thromboprophylaxis following THR or TKR. In contrast, the 2011 version of the AAOS guidelines makes no specific recommendations for pharmacologic agents.¹¹ Despite the availability of evidence-based guidelines with specific recommendations, physician compliance with these guidelines is low.¹²

Before the approval of rivaroxaban, the vitamin K antagonist warfarin was the only available oral option for thromboprophylaxis following THR or TKR. The use of warfarin can be challenging, because it requires frequent monitoring and maintaining a patient within a specified international normalized ratio (INR) range. Several factors may influence time-in-therapeutic range, including drug-drug and drug-food interactions and genetic polymorphisms of vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 (CYP)2C9.¹³ Warfarin does not provide short-term prophylaxis because of its delayed onset of action. It has been reported that 5 days after THR and TKR only about 30% of patients are within an INR of 2.0 to 3.0.¹⁴ Patients with an INR below 2.0 are at a 4- to 5-fold increased risk for VTE.¹⁴

Low-molecular-weight heparins, such as enoxaparin, do not require routine monitoring and have minimal drug interactions.¹⁵ The main drawback of LMWHs is their injectable mode of administration, which may influence prescribing habits and medication adherence. Patient education plays an essential role in ensuring adherence to LMWHs following orthopedic surgery.¹⁶