A study comparing enoxaparin and rivaroxaban used for routine venous thromboembolism (VTE) prophylaxis after primary total hip and knee arthroplasty (THA/TKA) found no statistically demonstrable difference in VTE rate or major bleeding complications.

The study, which was presented during the 2014 AAOS Annual Meeting, was one of the largest non–industry-funded studies comparing the two anticoagulants, according to author Nicholas B. Frisch, MD, MBA, of the Henry Ford Hospital in Detroit.

The investigators undertook the study when their institution switched from enoxaparin, a subcutaneously injected antithrombin III activator, to rivaroxaban, an oral Factor Xa inhibitor. Previous studies had indicated that rivaroxaban (marketed as Xarelto) decreases VTE rates with similar complications compared to enoxaparin (marketed as Lovenox). More recent studies, however, suggested potential complications associated with rivaroxaban, including increased risk of bleeding, wound complications, and return to the operating room.

Defining cohorts
The authors conducted a retrospective cohort study on 1,795 patients who underwent primary THA or TKA by one of six fellowship-trained surgeons at two academically affiliated hospitals. Patients were excluded if they met any of the following criteria:

• had a bilateral procedure
• had a partial arthroplasty (hip hemiarthroplasty, unicompartmental knee arthroplasty)
• had revision surgery
• were designated as a complex case
• took other anticoagulants (dabigatran, aspirin, clopidogrel, warfarin, heparin, fondaparinux)
• had less than 6 weeks follow-up
• had preoperative creatinine level of 1.2 or greater

After the exclusions, 1,089 patients were included in the study. All patients had received perioperative prophylactic antibiotics, wore thromboembolic deterrent stockings or mechanical compression stockings, and had been mobilized on postoperative day one. Routine outpatient physical therapy was prescribed.

Patients who underwent THA received pharmacologic VTE prophylaxis beginning the morning after surgery with either enoxaparin (40 mg subcutaneously daily for 21 days) or rivaroxaban (10 mg orally daily for 35 days). Patients who underwent TKA received either 30 mg of enoxaparin twice daily for 14 days or 10 mg rivaroxaban daily for 12 days.

“The baseline risk for thromboembolic events has been shown to extend longer for THA than TKA, and ACCP guidelines support longer duration prophylaxis for THA than TKA,” explained Dr. Frisch. “The median time of diagnosis for thromboembolic events is 7 days after TKA and 17 days after THA. We based the dosages on manufacturer recommendations and the literature supporting the efficacy and safety profiles at the specified amounts.”

No differences found
Researchers found no demonstrable differences in deep venous thrombosis (DVT) or pulmonary embolism (PE) between the two drug groups, regardless of the type of surgery performed. Among patients taking enoxaparin, the rate of DVT was 2.3 percent; among those taking rivaroxaban, it was 1.3 percent (P = 0.400). The rate of PE was 0.8 percent in the enoxaparin group and 0.3 percent in the rivaroxaban group (P = 0.679). Additionally, there were no statistical differences in major bleeding events between the two groups.

“One of the inherent challenges with determining the most effective agent for pharmacologic VTE prophylaxis is balancing the benefits with the potential complications, namely major bleeding and wound complications,” noted Dr. Frisch. “There is significant variability in the literature regarding the definition and rates of bleeding complications, making direct comparisons between studies challenging. For the purpose of this study, we defined major bleeding complication as postoperative hemorrhagic cerebrovascular event and blood transfusion.”

Dr. Frisch noted that an extensive debate remains regarding perioperative blood management and whether a conservative or liberal approach to transfusion results in better patient outcomes.

“No clear consensus has been reached regarding transfusion thresholds, and significant variability exists regarding optimal transfusion guidelines,” he said. At the study institution, the protocol is to transfuse symptomatic patients with hemoglobin levels less than 8g/dL and asymptomatic patients with hemoglobin levels less than 7g/dL. In this study, the transfusion rate between the groups was not significantly different (13.4 percent in the enoxaparin group and 15.5 percent in the rivaroxaban group).

Advantages over warfarin
Both enoxaparin and rivaroxaban have more predictable pharmacodynamics and a pharmacokinetic profile that does not require laboratory monitoring, giving them advantages over agents such as warfarin. Enoxaparin also has an advantage in patients with renal impairment.

However, noted Dr. Frisch, “Enoxaparin requires subcutaneous administration, which has been shown to potentially decrease patient compliance over the recommended duration of therapy. Furthermore subcutaneous administration has an inherent additional cost compared to oral medications, which is increased further by the twice-daily dosing. Enoxaparin also carries a risk of thrombocytopenia, while rivaroxaban does not.

“Once-daily oral dosing is an advantage of rivaroxaban,” he continued. “However, one of the arguments against the use of rivaroxaban for VTE prophylaxis is that it has no specific reversal agents.”

In terms of cost, one study found that rivaroxaban was associated with savings of $512 for THA prophylaxis and $466 for TKA prophylaxis, compared to enoxaparin, even though a generic enoxaparin has been available since July 2010. At the study institution, the cost of enoxaparin for THA prophylaxis was $134.29 per week compared to $87.87 for rivaroxaban. For TKA prophylaxis, the cost of enoxaparin was $187.14 per week, compared to $84.45 per week for rivaroxaban.

Coauthors for “Rivaroxaban Versus Enoxaparin for Venous Thromboembolism Prophylaxis After Total Hip and Knee Arthroplasty” are Michael A. Charters, MD; Nolan M. Wessell, MD; Christopher Dobson, BS; Clifford M. Les, DVM, PhD; and Craig D. Silverton, DO.

Disclosure information: Dr. Silverton—Biomet, Michigan Orthopaedic Society. The other authors report no conflicts.

Terry Stanton is a senior science writer for AAOS Now. He can be reached at tstanton@aaos.org

Bottom Line

• Some recent studies have suggested that potential complications may be associated with rivaroxaban, including increased risk of bleeding, wound complications, and return to the operating room.
• The present study reports on results when a hospital switched from subcutaneously injected enoxaparin to oral rivaroxaban for VTE prophylaxis in total joint replacement surgery.
• The switch resulted in no statistically demonstrable difference in VTE rate or major bleeding complications.
• The once-daily oral dosing for rivaroxaban results yields better patient compliance and considerable cost savings versus injected enoxaparin; one disadvantage of rivaroxaban is the absence of a reversing agent.