Introduction

The purpose of the present study was to identify risk factors for lag-screw cut-out following osteosynthesis of intertrochanteric fractures.

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 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: 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.

Rivaroxaban is an oral, direct Factor Xa inhibitor in clinical development for the prevention of VTE after major orthopaedic surgery. Data from three phase II trials of twice-daily (bid) rivaroxaban in patients undergoing elective, total hip or knee replacement were pooled to determine whether age, gender or weight affected the efficacy or safety of rivaroxaban, and thus whether dose adjustment would be necessary. Patients received 5–9 days of oral rivaroxaban (2.5–30 mg bid, post-operatively), or s.c. enoxaparin. A logistic regression model using total daily dose of rivaroxaban as a covariate, and adjusted for differences between dose groups with respect to study, age and gender, was used to estimate rates of the primary efficacy endpoint (DVT, PE or all-cause mortality; n=1380 intention-to-treat patients) and clinically relevant bleeding (major and non-major clinically relevant bleeding; safety population, n=1854). Rivaroxaban at total daily doses of 5–20 mg had similar efficacy and safety to enoxaparin. Overall, logistic regression showed a positive dose–response relationship with rivaroxaban for clinically relevant bleeding (p< 0.001), and a flat relationship for the primary efficacy endpoint (p=0.115). The risk of VTE increased with age – the efficacy endpoint was estimated to occur in 17.3–9.4%, 18.7–17.3% and 26.6–20.2% of patients aged < 60 yrs, 60–70 yrs and > 70 yrs receiving rivaroxaban (total daily dose 5–60 mg), respectively, in separate regression models. Age was also prognostic for clinically relevant bleeding with rates of 1.4–12.0% (< 60 yrs), 2.7–15.4% (60–70 yrs) and 5.7–15.4% (> 70 yrs). The rates are for a population distributed equally across the studies and genders. Incidences of the efficacy endpoint were higher in females (25.8–20.5%) than males (16.6–10.7%), while clinically relevant bleeding occurred more frequently in males (5.4–16.3%) than in females (1.7–11.6%), after adjustment for age. Weight was not prognostic for the efficacy endpoint or clinically relevant bleeding (p=0.87 and p=0.48, respectively, after adjustment for age, gender and study), nor did it modify the dose–response relationships with rivaroxaban. Incidences of the efficacy endpoint for a population of equal study and gender distribution and of mean patient age were 23.4–15.7% and 19.1–14.6% in patients weighing < 65 kg and ≥90 kg, respectively, with corresponding bleeding rates of 3.3–16.5% and 3.2–17.5%. This analysis indicates that age, gender or weight did not affect the dose–response relationships (or lack thereof) between rivaroxaban and the primary efficacy endpoint or clinically relevant bleeding. As expected, age was prognostic for VTE and bleeding. These findings suggest that rivaroxaban may not require dose adjustment for age, gender or weight in orthopaedic patients.

Routine prophylaxis is recommended to prevent venous thromboembolism (VTE) – manifesting as deep vein thrombosis (DVT) and/or pulmonary embolism (PE) – in patients undergoing major orthopaedic surgery. Rivaroxaban (BAY 59-7939) is a novel, oral, direct Factor Xa inhibitor in development for the prevention and treatment of VTE. The efficacy and safety of 5–9 days’ prophylaxis with rivaroxaban were investigated in three randomized, double-blind, phase IIb trials in patients undergoing elective, total hip or knee replacement (THR or TKR), relative to subcutaneous enoxaparin.

Two trials (one in patients undergoing THR, N=722; and one in patients undergoing TKR, N=621) investigated twice-daily (bid) rivaroxaban (at total daily doses of 5–60 mg); the third (in patients undergoing THR, N=873) investigated once-daily (od) rivaroxaban (at doses of 5, 10, 20, 30 or 40 mg od).

Rivaroxaban – at all doses tested – had similar efficacy to enoxaparin in the bid trials. This promising finding was strengthened by the od trial, in which the observed incidences of the primary efficacy endpoint (DVT, non-fatal PE or all-cause mortality) were lower in patients receiving rivaroxaban 5, 10, 20, 30 and 40 mg od (14.9%, 10.6%, 8.5%, 13.5% and 6.4%, respectively) than enoxaparin (25.2%). Although there was no significant dose–response relationship between rivaroxaban and the primary efficacy endpoint in these trials, there was with major VTE (proximal DVT, PE or VTE-related death; p=0.0072) in the od trial (incidences were 8.5%, 2.7%, 0.9%, 1.9% and 1.1% with rivaroxaban 5, 10, 20, 30 and 40 mg od, respectively, vs 2.8% with enoxaparin).

Significant dose–response relationships between rivaroxaban and major bleeding were observed in all three trials. In the bid trials, major bleeding rates with rivaroxaban were similar to those with enoxaparin at total daily doses of 5–20 mg. In the od trial, major bleeding occurred in 2.3%, 0.7%, 4.3%, 4.9% and 5.1% of patients receiving rivaroxaban 5, 10, 20, 30 and 40 mg od, respectively, and in 1.9% of those receiving enoxaparin.

Rivaroxaban was generally well tolerated in the bid and od trials, and the incidence of nausea and vomiting with early post-operative oral rivaroxaban administration was low for all doses tested.

The bid trials suggest that oral rivaroxaban at total daily doses of 5–20 mg may be a safe and effective alternative to enoxaparin for the prevention of VTE after major orthopaedic surgery. The od trial suggests that the more-convenient od regimen is feasible and that 10 mg od, a dose within the range identified by the bid trials, should be investigated further. As a result, oral rivaroxaban 10 mg od is currently being investigated in four phase III trials for the prevention of VTE after major orthopaedic surgery (the RECORD trials).

To target postoperative patients in need for prolonged pharmacologic thromboprophylaxis due to persistent coagulation activation, we developed and evaluated a qualitative test method, which detects the urinary excretion of prothrombin fragment 1+2 (uF1+2). The test was developed as a dip-stick device consisting of a one step rapid lateral flow immunoassay with visual readout on one test line and one control line. The assay time was between 5 and 10 minutes.

Spot urine samples were collected in 113 patients undergoing elective hip arthroplasty preoperatively and on day 5 after operation. Specimens were frozen immediately and stored until batch analysis. Pharmacologic thromboprophylaxis was administered according to national guidelines until day 7±2 after the operation. The results of the new dip-stick device were compared with the results of a laboratory based enzyme-linked-immunosorbent-assay (ELISA) method and a predetermined cut-off value. Patients were followed for development of vascular thrombotic complications/unexpected death until day 90 after the operation.

10 (8.8%) patients experienced an event during the study: 2 (1.8%) died unexpectedly and 8 (7.1%) had a vascular thrombotic event. All patients with clinical events had significantly raised postoperative levels of uF1+2. The clinical accuracy of the dip-stick test was acceptable with a sensitivity of 100% and a negative predictive value of 100%. Compared to the standard ELISA method the dip-stick test had a sensitivity of 93% and a specificity of 48%.

Laboratory ELISA analysis of urinary excretion of uF1+2 is neither feasible nor applicable in postoperative patients. Bed-side testing of persistent coagulation activation, however, could help to determine the need for prolonged thromboprophylaxis. The new dip-stick urine test was very easy to use, had a high negative predictive value and sensitivity and thus appears to be safe. However, the number of false positive test results prompts a fine-tuning of the test device. In terms of clinical applicability the test was acceptable. The study showed that about one third of the patients could be excluded from further extension of thromboprophylaxis beyond the first week.