May 5, 2009 (Hamilton, Ontario) — The RECORD4 trial of the new oral anticoagulant rivaroxaban (Xarelto, Johnson & Johnson/Bayer) in patients undergoing total knee arthroplasty has been published online May 1, 2009 in the Lancet .
The study, which was first presented, and reported by heartwire , last year at the European Federation of National Associations of Orthopaedics & Traumatology (EFORT) meeting, showed that oral rivaroxaban 10 mg once daily for 10 to 14 days was significantly superior to subcutaneous enoxaparin 30 mg given every 12 hours for the prevention of venous thromboembolism (VTE) after total knee arthroplasty.
Rivaroxaban is one of several new oral anticoagulants in development, which offer the first alternative to warfarin, which is widely used but has many drawbacks, including an unpredictable response and the need for constant monitoring. Rivaroxaban has recently been made available in Europe for the prevention of venous thromboembolism after surgery, and it is also approved in Canada. A US FDA advisory committee recommended approval of rivaroxaban in March for the prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing hip- and knee-replacement surgery. The drug is also in large-scale trials for the prevention of stroke in patients with atrial fibrillation and for the secondary prevention of cardiovascular events in ACS patients.
In the current paper, the authors, led by Dr Alexander Turpie (McMaster University, Hamilton, ON), explain that prophylaxis for venous thromboembolism for at least 10 days after total knee arthroplasty is recommended and that, given the trend for shorter hospital stays, a simple, effective, oral anticoagulant regimen for use in an outpatient setting would be beneficial. The RECORD studies were conducted to compare rivaroxaban with the current standard treatment (enoxaparin by subcutaneous injection) for the prevention of venous thromboembolism after orthopedic surgery. The authors note that RECORD4 differs from the previously reported RECORD1, 2, and 3 trials in that it compared rivaroxaban with the enoxaparin dose approved in North America for the prevention of venous thromboembolism after total knee arthroplasty (30 mg every 12 hours), whereas the previous RECORD trials compared the new drug with a lower dose of enoxaparin (40 mg once daily).
In the RECORD4 study, 3148 patients undergoing knee arthroplasty received either oral rivaroxaban 10 mg once daily, beginning six to eight hours after surgery, or subcutaneous enoxaparin 30 mg every 12 hours, starting 12 to 24 hours after surgery. Patients had mandatory bilateral venography between days 11 and 15. The primary efficacy outcome was the composite of any deep-vein thrombosis, nonfatal pulmonary embolism, or death from any cause up to day 17 after surgery. This was significantly reduced in the rivaroxaban group.
RECORD-4: Primary End Point
|Rivaroxaban||Enoxaparin||Absolute risk difference (95% CI)||p|
|6.9%||10.1%||-3.17 (-5.67 to -0.71)||0.0118|
Although there were more bleeding events with rivaroxaban, the differences compared with enoxaparin were not statistically significant.
RECORD4: Bleeding Results
|Outcome||Rivaroxaban (%)||Enoxaparin (%)||p|
|Major bleed or clinically relevant nonmajor bleed||3.0||2.3||0.1790|
The authors note that the low incidence of major bleeding events in this study compared with other similar studies could in part be attributed to the definition of bleeding used. In this study, major bleeding did not include bleeding leading to treatment cessation or surgical-site bleeding events unless they were fatal or required reoperation, a definition they say was agreed in advance with the relevant authorities to allow better assessment of clinically important bleeding events and was used consistently across the RECORD studies.
The adverse-event profiles of rivaroxaban and enoxaparin were similar. Six patients in each group (0.4%) died, and on-treatment alanine aminotransferase concentrations were more than three times the upper limit of normal in 1.3% of rivaroxaban patients and 2.6% of enoxaparin patients. The incidence of cardiovascular events during treatment and follow-up were similar in both groups.
Turpie et al note that the efficacy results of this study are in line with those of RECORD1 and RECORD3. "The improvements in efficacy in each of these studies were achieved without significant differences in major bleeding rates compared with enoxaparin. These findings suggest that rivaroxaban regimens provide better balance between efficacy and safety than do enoxaparin regimens," they write.
They add that previous phase 3 studies showed that the direct thrombin inhibitors ximelagatran and dabigatran did not prove noninferiority to enoxaparin 30 mg every 12 hours and the direct factor Xa inhibitor apixaban also did not meet prespecified noninferiority criteria, although event rates in the apixaban and enoxaparin groups were very similar.
Effect of VTE "Substantial"
In an accompanying editorial , Dr Richard Becker (Duke University School of Medicine, Durham, NC) points out that the overall effect of VTE after orthopedic surgery is substantial, with patients who suffer a VTE having longer hospital stays, needing systemic anticoagulation for six to 12 weeks, and potentially facing substantial physical limitations during rehabilitation and recovery. And in the long term, he notes that it has been suggested that patients with VTE have an increased risk of MI or stroke and maybe also of malignant disease. "Accordingly, reducing the occurrence of VTE must continue to be a high priority in drug development, national health quality, best-practice initiatives, and clinician-based care of patients. Clear progress has been achieved over the past decade, and oral drug-delivery platforms could represent a vital step forward," he says.
The RECORD4 trial was funded by Bayer Schering and Johnson & Johnson. Four of the authors are employees of Bayer Schering, and all other authors received honoraria as members of the steering committee and have served as consultants to Bayer Schering.
Heartwire from Medscape © 2009 Medscape, LLC
Cite this: RECORD4 Published: Rivaroxaban Superior to Enoxaparin in VTE Prevention - Medscape - May 05, 2009.