RECORD3 was a multicentre, phase III study designed to investigate the efficacy and safety of rivaroxaban – a novel, oral, once-daily, direct Factor Xa inhibitor – compared with subcutaneous enoxaparin for thromboprophylaxis in patients undergoing total knee arthroplasty (TKA).

Patients scheduled to undergo TKA (N=2,531) were randomized to receive either rivaroxaban 10 mg once daily (initiated 6–8 hours after surgery) or enoxaparin 40 mg once daily (initiated the evening before surgery, then given 6–8 hours after surgery), and daily thereafter for 10–14 days.

The primary efficacy outcome was the composite of any deep vein thrombosis (DVT; symptomatic or asymptomatic detected by mandatory, bilateral venography), non-fatal pulmonary embolism (PE) and all-cause mortality within 13–17 days after surgery.

Rivaroxaban significantly reduced the incidence of the primary efficacy outcome compared with enoxaparin (9.6% vs 18.9%, respectively; p< 0.001; relative risk reduction [RRR] 49%). Rivaroxaban significantly reduced the incidence of major VTE (the composite of proximal DVT, non-fatal PE and VTE-related death) compared with enoxaparin (1.0% vs 2.6%, p=0.01; RRR 62%), and the incidence of symptomatic VTE (0.7% vs 2.0%, p=0.005; RRR 66%). The incidence of bleeding events was similar in both groups (major bleeding: 0.6% and 0.5% in the rivaroxaban and enoxaparin groups, respectively; any on-treatment bleeding: 4.9% and 4.8%, respectively; haemorrhagic wound complications [the composite of excessive wound haematoma and surgical-site bleeding]: 2.0% and 1.9%, respectively). There were no deaths or PEs in the rivaroxaban group during the treatment period, and two deaths and four PEs in the enoxaparin group.

Rivaroxaban was significantly more effective than enoxaparin for the prevention of VTE after TKA, with a similar rate of bleeding. The oral, direct Factor Xa inhibitor rivaroxaban, given once daily as a fixed, unmonitored dose of 10 mg, has the potential to change clinical practice for thromboprophylaxis after TKA.

Rivaroxaban is a novel, oral, once-daily, direct Factor Xa inhibitor in advanced clinical development. RECORD1 was a multinational, randomized, double-blind, double-dummy, phase III study investigating the efficacy and safety of extended thromboprophylaxis with rivaroxaban compared with subcutaneous enoxaparin following THR.

Patients (N=4541) were randomized to receive oral rivaroxaban 10 mg (6–8 hours after surgery and once daily thereafter) or subcutaneous enoxaparin 40 mg (administered the evening before surgery, 6–8 hours after surgery, and once daily thereafter) for 35±4 days. The primary efficacy outcome was the composite of deep vein thrombosis (DVT: symptomatic or detected by mandatory, bilateral venography if asymptomatic), non-fatal pulmonary embolism (PE), and all-cause mortality up to day 36±6. Major venous thromboembolism (VTE), the composite of any DVT, non-fatal PE and VTE-related death, was a secondary outcome. Safety endpoints included major and non-major bleeding while receiving study medication.

Rivaroxaban significantly reduced the incidence of the primary efficacy outcome compared with enoxaparin (1.1% vs 3.7%, respectively; p< 0.001; relative risk reduction [RRR] 70%). Rivaroxaban also significantly reduced the incidence of major VTE compared with enoxaparin (0.2% vs 2.0%, respectively; p< 0.001; RRR 88%). There were no significant differences in the incidence of major bleeding (0.3% vs 0.1%; p=0.178) or non-major bleeding (5.8% vs 5.8%; p=1.000) between rivaroxaban and enoxaparin, respectively. There was no evidence of liver safety issues associated with rivaroxaban.

Thromboprophylaxis with once-daily, oral rivaroxaban was significantly more effective than subcutaneous enoxaparin following THR without an increased risk of bleeding. This trial demonstrates the efficacy and safety of a fixed, unmonitored, once-daily dose of oral rivaroxaban for extended thromboprophylaxis after THR.

Introduction: Four randomized, double-blind, phase III studies (RECORD1–4) investigated the oral, direct Factor Xa inhibitor rivaroxaban for the prevention of venous thromboembolism (VTE) after major orthopaedic surgery. Patients (N=12,729) were randomized to receive oral rivaroxaban 10 mg once daily or subcutaneous enoxaparin 40 mg once daily (RECORD1–3), or 30 mg twice daily (RECORD4). In RECORD1 and 2, patients undergoing total hip arthroplasty received rivaroxaban for 31–39 days. Enoxaparin was given for 31–39 days in RECORD1, 10–14 days followed by placebo in RECORD2. In RECORD3 and 4, patients undergoing total knee arthroplasty received prophylaxis for 10–14 days. After prophylaxis, all patients were followed up for a further 30–35 days. Rivaroxaban significantly reduced the incidence of the primary efficacy outcome for the individual studies (total VTE; composite of any deep vein thrombosis, non-fatal pulmonary embolism [PE] and all-cause mortality) compared with the enoxaparin regimens, with similar rates of major bleeding.

Methods: A pre-specified pooled analysis of all four trials was performed on all randomized patients who received at least one dose of double-blind study medication to evaluate the effect of rivaroxaban on the composite of symptomatic VTE and all-cause mortality (primary outcome for pooled analysis), and bleeding. This outcome was analysed at day 12±2 in the active treatment pool (enoxaparin-controlled in all studies) and in the total study duration pool (including follow-up after treatment).

Results: Rivaroxaban significantly reduced the incidence vs enoxaparin of the composite of symptomatic VTE and death (day 12±2: 0.47% vs 0.97%, respectively, p=0.001; total study duration: 0.81% vs 1.6%, respectively, p< 0.001) and the composite of PE and death (day 12±2: 0.19% vs 0.39%, respectively, p=0.049; total study duration: 0.47% vs 0.76%, respectively, p=0.039). The rates of major bleeding with the rivaroxaban and enoxaparin regimens were 0.34% and 0.21%, respectively, p=0.175 at day 12±2 and at total study duration were 0.44% and 0.27%, respectively, p=0.135. Rivaroxaban also reduced the composite of death, infarction, stroke, symptomatic VTE and major bleeding vs enoxaparin (total study duration: 1.6% vs 2.2%, respectively, p=0.006).

Conclusion: Rivaroxaban reduced the composites of major clinical outcomes compared with enoxaparin regimens, with similar rates of major bleeding, in patients undergoing major orthopaedic surgery.

Introduction: Four randomized, double-blind phase III studies (RECORD1–4) investigated the oral, direct Factor Xa inhibitor rivaroxaban for the prevention of venous thromboembolism (VTE) after elective total hip and total knee arthroplasty (THA and TKA). Patients (N=12,729) were randomized to receive oral rivaroxaban 10 mg once daily, or subcutaneous enoxaparin 40 mg once daily (RECORD1–3), or 30 mg twice daily (RECORD4). Those undergoing THA received rivaroxaban or enoxaparin for 31–39 days in RECORD1, and rivaroxaban for 31–39 days or enoxaparin for 10–14 days followed by placebo in RECORD2. In RECORD3 and 4 (TKA), prophylaxis was for 10–14 days.

Methods: A prespecified pooled analysis of all four studies evaluated the effect of rivaroxaban on the composite of symptomatic VTE and all-cause mortality, and bleeding, relative to enoxaparin. The present subgroup analysis investigated potential drug–drug interactions with concomitant non-steroidal anti-inflammatory drugs (NSAIDs) or acetylsalicylic acid (ASA) – commonly used pain medications known to affect bleeding risk. The risk of on-treatment bleeding in the total study duration pool of all four RECORD studies was investigated. These prespecified analyses focused on on-treatment, adjudicated bleeding events, any bleeding, and the composite of major bleeding and clinically relevant non-major bleeding – after the first tablet intake (rivaroxaban or matching placebo). Co-medication use was evaluated over time. Relative bleeding rates with and without co-medication were calculated separately for the rivaroxaban and enoxaparin/placebo groups. Time after surgery (day of surgery was day 1) was stratified into three periods (days 1–3, days 4–7 and day 7 up to 2 days after the last dose), based on the decreasing risk with time of a first bleeding event after surgery and because prevalence of co-medication use can vary over time. Bleeding rates were recorded for each time period over the at-risk period (the day of surgery until the last day of double-blind study medication intake +2 days or until initial event onset). The ratio of the bleeding rate for co-medication exposed vs unexposed patient-days in the rivaroxaban group was compared with the corresponding rate ratio for the enoxaparin/placebo group for bleeding events (Mantel–Haenszel methods).

Results: Concomitant use of ASA in the rivaroxaban groups showed rate ratios similar to those in the enoxaparin/placebo group (1.32 and 1.40, respectively, for any bleeding). Rate ratios were also similar with concomitant use of NSAIDs (1.22 in both groups, for any bleeding).

Conclusion: In the RECORD1–4 subanalysis, there was no indication of increased bleeding associated with the use of these co-medications in patients taking rivaroxaban, compared with enoxaparin.

Introduction: Rivaroxaban is a novel, oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. In this phase III trial, the efficacy and safety of thromboprophylaxis with rivaroxaban was compared with enoxaparin in patients undergoing total knee replacement (TKR).

Methods: In RECORD3 – a randomized, double-blind trial – patients received rivaroxaban 10 mg 6–8 hours after surgery and once daily (od) thereafter, or enoxaparin 40 mg od beginning the evening before surgery; both were continued for 10–14 days. The primary efficacy outcome was the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE) and all-cause mortality. Secondary efficacy outcomes included major venous thromboembolism (VTE; the composite of proximal DVT, PE and VTE -related death) and symptomatic VTE. The primary safety outcome was major bleeding, and other safety outcomes included any on-treatment bleeding and haemorrhagic wound complications (the composite of excessive wound haematoma and surgical-site bleeding).

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 was reported in 9.6% of patients receiving rivaroxaban and 18.9% of patients receiving enoxaparin. This equated to a relative risk reduction of 49% (p< 0.001) with rivaroxaban compared with enoxaparin. The incidence of major VTE was also significantly reduced with rivaroxaban compared with enoxaparin (relative risk reduction 62%, p=0.016). The incidence of symptomatic VTE was significantly lower in the rivaroxaban group than in the enoxaparin group (p=0.005). Major bleeding rates were 0.6% and 0.5% in the rivaroxaban and enoxaparin groups, respectively, and rates of any on-treatment bleeding were 4.9% and 4.8%, respectively. The incidence of haemorrhagic wound complications was 2.1% in the rivaroxaban group and 1.9% in the enoxaparin group.

Conclusions: Rivaroxaban was significantly more effective than enoxaparin for the prevention of VTE after TKR, with a similar safety profile. The oral, direct Factor Xa inhibitor rivaroxaban, given as a fixed, unmonitored dose, may have the potential to change clinical practice for thromboprophylaxis after TKR.

Introduction: Venous thromboembolism (VTE) is a common, potentially fatal complication of major orthopaedic surgery. Although pharmacological thromboprophylaxis is recommended following total hip replacement (THR) for a minimum of 10 days, and up to 35 days, its extended use is not universally accepted – an effective, safe and convenient, oral anticoagulant would improve implementation of these recommendations. This trial compared short-term thromboprophylaxis using enoxaparin with extended thromboprophylaxis using rivaroxaban – a once-daily, oral, direct Factor Xa inhibitor – after THR, in the largest, prospective, randomized clinical trial conducted to date for the evaluation of the risk/benefit of extended prophylaxis.

Method: In this global, double-blind trial, 2509 patients undergoing THR were randomized to receive either subcutaneous enoxaparin 40 mg once daily (od), started the evening before surgery and continued for 10–14 days, followed by placebo until day 35±4 (short-term prophylaxis), or oral rivaroxaban 10 mg od, started 6–8 hours after surgery and continuing for 35±4 days (extended prophylaxis). Mandatory, bilateral venography was conducted on day 36±4. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality. The main secondary efficacy endpoint was major VTE (the composite of proximal DVT, non-fatal PE, and VTE-related death). Safety endpoints included the incidence of major and non-major bleeding.

Results: The incidence of the primary efficacy endpoint was significantly reduced with extended thromboprophylaxis with rivaroxaban compared with short-term enoxaparin (2.0% and 9.3%, respectively; p< 0.001; relative risk reduction [RRR] 79%), as was major VTE (0.6% versus 5.1%; p< 0.001; RRR 88%). The incidence of major bleeding was the same in both groups (0.1%). Non-major bleeding was reported in 6.5% of patients who received extended thromboprophylaxis with rivaroxaban and in 5.5% of those treated with short-term enoxaparin.

Conclusion: Extended duration thromboprophylaxis with rivaroxaban is both significantly more effective and adds no disadvantage, in terms of bleeding, when compared with short-term prophylaxis. These data suggest that extended thromboprophylaxis provides substantial benefits to patients undergoing THR and rivaroxaban provides a safe and effective option for this strategy.

Introduction: After total hip replacement (THR), thromboprophylaxis for at least 10 days and for up to 35 days is recommended – yet a convenient, oral anticoagulant is not currently available. Rivaroxaban – a once-daily, oral, direct Factor Xa inhibitor with a predictable clinical profile – is in advanced clinical development. RECORD1, a multinational, randomized, double-blind, double-dummy, phase III study, compared once-daily oral rivaroxaban with subcutaneous enoxaparin for 5 weeks following THR.

Methods: In total, 4541 patients were randomized to receive oral rivaroxaban 10 mg (6–8 hours after surgery and once daily thereafter), or 40 mg enoxaparin (administered subcutaneously the evening before surgery, resumed 6–8 hours after surgery, and continued once daily). Thromboprophylaxis was administered for 35±4 days; mandatory, bilateral venography was conducted the next day. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), nonfatal pulmonary embolism (PE), and all-cause mortality. Safety endpoints included major and non-major bleeding during the active treatment period.

Results: The incidence of the composite of DVT, PE, and all-cause mortality was significantly lower for rivaroxaban compared with enoxaparin (1.1% vs 3.7%, respectively; p< 0.001; relative risk reduction [RRR] 70%). The incidence of major VTE was also significantly lower for rivaroxaban compared with enoxaparin (0.2% vs 2.0%, respectively; p< 0.001; RRR 88%). There were no significant differences in the incidence of major bleeding (0.3% vs 0.1%; p=0.178) or non-major bleeding (5.8% vs 5.8%; p=1.000) between rivaroxaban and enoxaparin, respectively. There was no evidence of cardiac or liver safety issues.

Conclusions: Following THR, thromboprophylaxis with once-daily, oral rivaroxaban was shown to be significantly more effective than subcutaneous, once-daily enoxaparin – without an increased risk of bleeding. This trial demonstrates the efficacy and safety of oral rivaroxaban using a fixed, unmonitored, once-daily dose for extended thromboprophylaxis after THR.