Abstract

Introduction Rivaroxaban is a novel, oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. In RECORD3, a phase III trial, the efficacy and safety of once-daily (od) rivaroxaban was compared with od enoxaparin for the prevention of venous thromboembolism (VTE) in patients undergoing total knee arthroplasty (TKA).

MethodsIn this multicenter, double-blind, double-dummy trial, patients undergoing TKA were randomized to receive either oral rivaroxaban 10 mg od or subcutaneous enoxaparin 40 mg od. Enoxaparin was initiated 12 hours before surgery, and rivaroxaban 6–8 hours after surgery; both were continued for 10–14 days. The primary outcome was the composite of deep vein thrombosis (DVT), pulmonary embolism (PE), and all-cause mortality. Secondary efficacy outcomes included major VTE (the composite of proximal DVT, PE and VTE-related death) and symptomatic VTE. The main safety outcome was major bleeding, and secondary outcomes included non-major bleeding and adverse events.

Results A total of 2531 patients were randomized; 2459 were eligible for inclusion in the safety population and 1702 for the modified intention-to-treat population. The primary efficacy outcome occurred in 9.6% of patients receiving rivaroxaban compared with 18.9% of those receiving enoxaparin (relative risk reduction 49%; p<0.001; Table). Rivaroxaban was also significantly more effective than enoxaparin at reducing major VTE, with a relative risk reduction of 62%. Symptomatic VTE was also lower with rivaroxaban than with enoxaparin. The incidences of major and non-major bleeding were similar in both the rivaroxaban and enoxaparin groups, as was the incidence of other adverse events. During the treatment period, there were no deaths or PEs in the rivaroxaban group, and two deaths and four PEs occurred in the enoxaparin group.

Conclusions Rivaroxaban was superior to enoxaparin for the prevention of VTE after TKA in this study, with a similar, low rate of bleeding. This is the first study to demonstrate the safety and efficacy of a fixed, unmonitored regimen of an oral, direct Factor Xa inhibitor - rivaroxaban - for the prevention of VTE after major orthopaedic surgery.

Rivaroxaban 10 mg od % (n/N)Enoxaparin 40 mg od % (n/N)Relative risk reduction (%)p -value for difference
aModified intention-to-treat-population; bModified intention-to-treat population valid for major VTE analysis; cSafety population who underwent surgery; dSafety population; *Calculated for the absolute risk difference 
DVT, non-fatal PE, and all-cause mortalitya 9.6% (79/824) 18.9% (166/878) 49% p <0.001 
Major VTEb 1.0% (9/908) 2.6% (24/925) 62% p =0.016 
Symptomatic VTEc 0.7% (8/1201) 2.0% (24/1217) 66% p =0.005 
Major bleedingd 0.6% (7/1220) 0.5% (6/1239) p =0.774* 
Non-major bleedingd 4.3% (53/1220) 4.4% (54/1239) p =0.990* 
Rivaroxaban 10 mg od % (n/N)Enoxaparin 40 mg od % (n/N)Relative risk reduction (%)p -value for difference
aModified intention-to-treat-population; bModified intention-to-treat population valid for major VTE analysis; cSafety population who underwent surgery; dSafety population; *Calculated for the absolute risk difference 
DVT, non-fatal PE, and all-cause mortalitya 9.6% (79/824) 18.9% (166/878) 49% p <0.001 
Major VTEb 1.0% (9/908) 2.6% (24/925) 62% p =0.016 
Symptomatic VTEc 0.7% (8/1201) 2.0% (24/1217) 66% p =0.005 
Major bleedingd 0.6% (7/1220) 0.5% (6/1239) p =0.774* 
Non-major bleedingd 4.3% (53/1220) 4.4% (54/1239) p =0.990* 

Author notes

Disclosure:Employment: Frank Misslewitz and Tiemo J Bandel: Bayer HealthCare AG. Consultancy: All authors: Bayer HealthCare. Research Funding: Walter Ageno: Italian Ministry of University and Research. All authors: Bayer HealthCare AG. Honoraria Information: Walter Ageno: sanofi-aventis, GlaxoSmithKline, Bayer HealthCare AG, Italfarmaco. Membership Information: Walter Ageno and Michael Lassen: Bayer HealthCare AG.