Rivaroxaban superior to enoxaparin in preventing VTE after knee arthroplasty

Results from the Regulation of Coagulation in Orthopaedic Surgery to Prevent Deep Vein Thrombosis and Pulmonary Embolism 4 (RECORD4) trial published in Lancet demonstrated that rivaroxaban 10 mg once daily is superior to subcutaneous (SC) enoxaparin in preventing venous thromboembolism (VTE) after total knee arthroplasty.

This multicenter, randomized, double-blind trial enrolled patients aged at least 18 years who were scheduled to undergo total knee arthroplasty. Patients were excluded if they had active bleeding, a high risk of bleeding, or a disorder contradicting enoxaparin use or possibly necessitating an enoxaparin dose adjustment. Patients were randomized to treatment with rivaroxaban 10 mg once daily or SC injections of enoxaparin 30 mg every 12 hours. Patients randomized to rivaroxaban received placebo injections, and those randomized to enoxaparin received placebo tablets. Rivaroxaban treatment was initiated 6 to 8 hours after wound closure or adequate hemostasis was achieved and was then administered every 22 to 26 hours in the evening. Enoxaparin treatment was initiated 12 to 24 hours after wound closure and was then administered every 10 to 14 hours. The day of surgery was designated Day 1, and treatment was continued until the evening before venography. Follow-up continued through 30 to 35 days after the last dose.

     The primary efficacy end point was a composite of any deep vein thrombosis (DVT), nonfatal pulmonary embolism (PE), or death from any cause up to Day 17 after surgery. A secondary end point was major venous thromboembolism (VTE) (including proximal DVT, nonfatal PE, or death related to venous thromboembolism). DVT was assessed by systematic, ascending, bilateral venography. Suspected PE was confirmed by pulmonary angiography, ventilation-perfusion lung scintigraphy with chest radiography, or contrast-enhanced spiral computed tomography (CT). The incidence of major bleeding between the first dose and 2 days after the last dose was assessed as a safety end point.

     A total of 3,148 patients were randomized to treatment; 1,742 patients were included in the per-protocol population, and 1,924 patients were included in the modified intent-to-treat (ITT) population. In the per-protocol population, 58 rivaroxaban-treated patients of 864 with venograms adequate for assessment experienced the primary end point versus 82 of 878 enoxaparin-treated patients (weighted absolute RR=2.71%; 95% CI, 0.17%–5.25%); noninferiority of rivaroxaban based on limit of –4%, P<.0001; superiority of rivaroxaban, P=.0362). In the modified ITT population, 67 of 965 rivaroxaban-treated patients experienced the primary end point versus 97 of 959 enoxaparin-treated patients (weighted absolute RR, 3.19%; 95% CI, 0.71%–5.67%; superiority of rivaroxaban, P=.0118).

     The secondary end point of major VTE occurred in 11 of 1,011 rivaroxaban-treated patients and in 15 of 1,020 enoxaparin-treated patients in the per-protocol population (weighted absolute RR=0.37%; 95% CI, –0.60% to 1.34%; noninferiority of rivaroxaban based on limit of –1.5%, P<.0001; superiority of rivaroxaban, P=.4556). In the mITT population, 13 of 1,122 rivaroxaban-treated patients and 22 of 1,112 enoxaparin-treated patients experienced major venous thromboembolism (weighted absolute RR=0.80%; 95% CI, –0.22% to 1.82%; superiority of rivaroxaban, P=.1237).

     Ten rivaroxaban-treated and 4 enoxaparin-treated patients had major bleeding (weighted absolute risk increase=0.39%; 95% CI, –0.09% to 0.88%; P=.1096). Adverse events were similar between the rivaroxaban- and enoxaparin-treated groups.

     The authors discussed several limitations of the study, including the low number of venograms adequate for assessment and the exclusion of surgical site bleeding from the major bleeding definition. They stated, however, that sensitivity analyses did not demonstrate an association between treatment effect and the rate of venograms adequate for assessment, and the inclusion of hemorrhagic wound complications as a secondary bleeding outcome would capture surgical site bleeding data.

Source
Turpie AGG, Lassen MR, Davidson BL, et al; for the RECORD4 investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): A randomised trial. Lancet. May 2009 [Epub ahead of print].