Once-Daily Oral Rivaroxaban Compared with Subcutaneous Enoxaparin Every 12 Hours for Thromboprophylaxis after Total Knee Replacement: RECORD4

Abstract Rivaroxaban is an oral, direct Factor Xa inhibitor that has been evaluated in the RECORD phase III clinical trial program for the prevention of venous thromboembolism (VTE) in major orthopaedic surgery. RECORD3 (Lassen M, et al. N Engl J Med2008;358:2776–2786) showed that oral rivaroxaban 10 mg once daily (od) given post-operatively significantly reduced VTE after total knee replacement (TKR), compared with subcutaneous (s.c.) enoxaparin 40 mg od initiated pre-operatively, with similar rates of bleeding. RECORD4 was designed to determine the efficacy and safety of rivaroxaban compared with enoxaparin 30 mg administered twice daily after TKR. Patients (N=3,148) were randomized to receive either oral rivaroxaban 10 mg od (initiated 6–8 hours after surgery) or s.c. enoxaparin 30 mg every 12 hours (initiated 12 to 24 hours after surgery) for 10 to 14 days. Patients underwent mandatory, bilateral venography between day 11 and day 15. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality up to day 17. The primary efficacy analysis was a test for non-inferiority in the per-protocol population (n=1,702), followed by a test for superiority in the modified intention-to-treat population (n=1,924) (if non-inferiority was established in the per-protocol population). The main secondary efficacy endpoint was major VTE: the composite of proximal DVT, non-fatal PE, and VTE-related death. Treatment-emergent major bleeding observed no later than two days after the last intake of study was the main safety endpoint. The results are shown in the table. Rivaroxaban significantly reduced the incidence of the primary efficacy outcome compared with enoxaparin (6.9% vs 10.1%, respectively; p=0.012; relative risk reduction 31%). Rivaroxaban was non-inferior to enoxaparin for the prevention of major VTE in the per-protocol population (p<0.001). The observed incidences of major VTE and symptomatic VTE in those receiving rivaroxaban or enoxaparin were 1.2% vs 2.0% (p=0.124), and 0.7% vs 1.2% (p=0.187), respectively, and the rates of major bleeding were 0.7% vs 0.3% (p=0.110) respectively, and major and clinically relevant non-major bleeding 3.0% vs 2.3% (p=0.179) in the rivaroxaban and enoxaparin treated groups, respectively. The data demonstrate that rivaroxaban has superior efficacy to enoxaparin 30 mg administered every 12 hours for the prevention of VTE after TKR, without significantly increasing the risk of bleeding. Endpoint Rivaroxaban10 mg od % (n/N) Enoxaparin30 mg q12h % (n/N) p-value for differenced aModified intention-to-treat population bModified intention-to-treat population valid for major VTE analysis cSafety population dCalculated for the absolute risk difference DVT, non-fatal PE, and all-cause mortalitya 6.9% (67/965) 10.1% (97/959) 0.012 Major VTEb 1.2% (13/1,122) 2.0% (22/1,112) 0.124 Symptomatic VTEc 0.7% (11/1,526) 1.2% (18/1,508) 0.187 Major bleedingc 0.7% (10/1,526) 0.3% (4/1,508) 0.110 Any non-major bleedingc 10.2% (155/1,526) 9.2% (138/1,508) – Major and clinically relevant non-major bleedingc 3.0% (46/1526) 2.3% (34/1,508) 0.179

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