BACKGROUND: Thromboprophylaxis for at least 10 days and for up to 4–5 weeks is recommended after total hip arthroplasty (THA). Rivaroxaban is an oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. RECORD1 was a phase III, multinational, randomized, double-blind, double-dummy trial, conducted to determine the efficacy and safety of oral rivaroxaban, compared with subcutaneous enoxaparin, for 5 weeks of thromboprophylaxis in patients undergoing THA. METHODS: Patients received rivaroxaban 10 mg beginning 6–8 hours after surgery and once daily (od) thereafter, or enoxaparin 40 mg od, beginning the evening before surgery (restarting 6–8 hours after surgery). Therapy continued for 35±4 days and mandatory, bilateral venography was conducted the next day. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality. The primary efficacy analysis was a test for non-inferiority in the per-protocol (PP) population, followed by a test for superiority in the modified intention-to-treat (mITT) population. The main secondary efficacy endpoint was major venous thromboembolism (VTE): the composite of proximal DVT, non-fatal PE and VTE-related death. Major and non-major bleeding during the active treatment period were the primary and secondary safety endpoints, respectively. RESULTS: A total of 4541 patients were randomized; 4433 were eligible for the safety population, 3153 for the mITT population, and 3029 for the PP population. The criteria for non-inferiority were met and testing for superiority was performed. Rivaroxaban significantly reduced the incidence of the primary efficacy endpoint (p<0.001) and major VTE (p<0.001), compared with enoxaparin, in the mITT population (Table). The incidence of major and non-major bleeding events was similar in both groups (Table). CONCLUSIONS: Rivaroxaban was significantly more effective than enoxaparin for extended prophylaxis after THA, with a similar safety profile. This is the first pivotal trial to demonstrate the efficacy and safety of a fixed, unmonitored dose of an oral, direct Factor Xa inhibitor - rivaroxaban - for extended thromboprophylaxis after THA.
Thromboprophylaxis after joint replacement surgery is evidence-based standard care. Usually, when thromboprophylaxis regimens with new anticoagulants have been more effective than existing standard practice they have also caused increased bleeding. Apixaban, a novel orally administered factor Xa inhibitor, has been evaluated in three phase 3 randomized, double-blind, double-dummy clinical trials (the ADVANCE studies) for the prevention of venous thromboembolism (VTE) after hip or knee replacement. A pre-specified aim of this program, in order to provide more precise estimates of the incidences of major VTE, bleeding, and the additional safety outcomes of myocardial infarction, stroke, and liver function, was to combine data from the two trials comparing apixaban 2.5 mg twice daily with the same enoxaparin regimen of 40 mg once daily (ADVANCE-2 and 3). Major VTE was defined a priori as the composite of adjudicated symptomatic or asymptomatic proximal deep-vein thrombosis (popliteal, femoral, or iliac vein thrombosis), non-fatal pulmonary embolism, and VTE-related death, counted if they occurred during the intended treatment period for each trial or within 2 days after the last dose of study medication, whichever was longer. The bleeding outcomes of major bleeding (adapted from ISTH criteria), clinically relevant non-major bleeding, and the composite of major and clinically relevant non-major bleeding, were counted if they occurred during the treatment period or within 2 days after the last dose of study medication. In both studies, subcutaneous enoxaparin (or placebo) was started 12±3 hours before operation, and resumed after surgery according to the investigator's standard of care, and oral apixaban (or placebo) was initiated 12 to 24 hours after wound closure (typically on the morning after surgery). Study medications were continued for 10 to 14 days after knee arthroplasty in ADVANCE- 2, and for 32 to 38 days after hip replacement in ADVANCE- 3. In both studies, mandatory bilateral venography was done at the end of the intended treatment period to assess the presence or absence of asymptomatic deep-vein thrombosis, and clinically suspected VTE was confirmed or excluded by objective testing. Patients were followed-up 30±5 and 60±5 days after the last dose of study medication. All venograms and all episodes of suspected VTE, bleeding, myocardial infarction, stroke, or death were adjudicated without knowledge of assigned treatment by an independent central adjudication committee. The site of bleeding was analysed as reported by the investigator. The pooled analysis was stratified by the type of joint replacement (hip or knee) for statistical calculations. A total of 8,564 patients were randomized in the ADVANCE-2 and 3 trials. Major VTE occurred in 23 of 3,394 evaluable patients (0.68%) in the apixaban group and in 51 of 3,394 (1.50%) evaluable patients in the enoxaparin group (absolute risk difference, -0.76%, 95% CI, -1.23% to -0.30%). Major bleeding occurred in 31 of 4,174 patients (0.74%) who received apixaban (18 occurred before the first dose) and in 32 of 4,167 patients (0.77%) given enoxaparin (absolute risk difference -0.02%, 95% CI, -0.40% to 0.35%). Major bleeding at the surgical site occurred in 26 apixaban and 27 enoxaparin patients (absolute risk difference -0.02%, 95% CI, -0.37% to 0.32%). The composite of major or clinically relevant non-major bleeding occurred in 182 patients (4.36%) given apixaban, compared with 206 patients (4.94%) given enoxaparin (absolute risk difference -0.58%, 95% CI, -1.49% to 0.32%); these bleeding events occurred at the surgical site in 135 (3.23%) apixaban patients, and in 155 (3.72%) enoxaparin patients (absolute risk difference -0.49%, 95% CI, -1.27% to 0.30%). Myocardial infarction or stroke during treatment or follow-up occurred in 13 patients (0.31%) in the apixaban group and in 10 patients (0.24%) in the enoxaparin group (absolute risk difference 0.07%, 95% CI, -0.15% to 0.30%). Elevated levels (>3 times upper normal limit) of enzymes ALT or AST occurred in 2.2% and 2.8% of apixaban patients respectively, and in 3.0% and 2.8% of enoxaparin patients respectively. The apixaban regimen was more effective than enoxaparin 40 mg once daily for preventing major VTE, without increased bleeding, and has the clinical advantages of oral administration and later initiation 12 to 24 hours post-operatively.
OBJECTIVE: To compare the effects of short-term and long-term thromboprophylaxis after total hip replacement on coagulation indicators in plasma sampled before and 1, 7 and 35 days post-operation.
METHODS: A total of 40 patients scheduled for elective total hip replacement were randomly assigned into the short-term (n = 20) or long-term (n = 20) thromboprophylaxis groups on oral rivaroxaban 10 mg once daily for 7 or 35 days. The primary efficacy hemostatic variables included thrombin-antithrombin complexes (TAT), prothrombin fragment 1+2 (F1t2), D-dimer and fibrinogen (Fib) preoperatively and at Days 1, 7 and 35 postoperatively. And ultrasonography was performed on all patients preoperatively and at days 7 and 35 postoperatively to exclude deep vein thrombosis of lower extremities.
RESULTS: None of them had deep vein thrombosis (DVT) of lower extremities. Among them, TAT, F1+2, D-dimer and Fib post-operation were higher than those preoperative baseline values. TAT and D-dimer peaked at day 1 postoperatively while the peaks of F1+2 and Fib appeared at day 7 postoperatively. At Day 35 post-operation, the levels of TAT and F1+2 in the long-term thromboprophylaxis group were significantly lower than those of the short-term thromboprophylaxis group (P < 0.05).
CONCLUSION: The status of hypercoagulability may sustain at least 35 days after total hip replacement. Though not completely eliminated, it can still be reduced by prolonged thromboprophylaxis. However, according to ultrasonography, the effects of short-term and long-term thromboprophylaxis on the incidence rate of DVT remain to be further explored.
BACKGROUND: New oral anticoagulants for thromboprophylaxis after hip or knee arthroplasty have been given as fixed-dose regimens.
OBJECTIVE: To evaluate the consistency of the antithrombotic efficacy and bleeding risk of apixaban 2.5 mg twice daily compared with enoxaparin 40 mg once daily after knee or hip arthroplasty across the clinical characteristics of age, gender, body weight, body mass index (BMI) and creatinine clearance.
METHODS: The pooled results of the ADVANCE-2 (knee arthroplasty) and -3 (hip arthroplasty) randomized trials were used to evaluate if treatment had a statistically significantly different effect (P < 0.10) on major venous thromboembolism (VTE) and bleeding for the characteristics of age, gender, body weight, BMI and creatinine clearance. Both univariate analysis and multivariate logistic regression were used.
RESULTS: Univariate analyses identified statistically significant interactions for age and major VTE (P = 0.09); for both age (P = 0.07) and body weight (P = 0.07) and the outcome of major bleeding; and for creatinine clearance (P = 0.03) and the composite outcome of major and clinically relevant non-major bleeding. Estimates of these possible differences were not precise, with wide 95% confidence intervals (CIs) that included a zero difference for several subgroups. Multivariate logistic regression analysis did not detect a statistically significant interaction for any outcomes.
CONCLUSIONS: This analysis found no convincing evidence that age, weight, gender, BMI or creatinine clearance influenced the balance of benefit to risk for apixaban compared with enoxaparin. Because only 5% of patients had a creatinine clearance between 30 and 50 mL min(-1), further data are needed in such patients.
BACKGROUND: Patients receiving anticoagulants could be at higher risk of compressive haematoma with neuraxial anaesthesia use. The phase III RECORD programme compared rivaroxaban with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement surgery in more than 12,500 patients. This observational analysis evaluated the risk of neuraxial haematoma after neuraxial anaesthesia in patients receiving rivaroxaban or enoxaparin using pooled RECORD1-4 data.
METHODS: The incidences of intraspinal bleeding or haemorrhagic puncture were recorded as part of the criteria for major bleeding (the primary safety outcome in the RECORD studies). Incidences of allogeneic transfusion and venous thromboembolism by type of anaesthesia were also recorded.
RESULTS: No compressive haematomas occurred in rivaroxaban-treated patients (10 mg once daily started 6-8 h after surgery) who underwent neuraxial anaesthesia (n = 4086). Among enoxaparin-treated patients (n = 4090), one compressive spinal haematoma requiring laminectomy occurred after epidural catheter removal in an elderly female patient with renal insufficiency undergoing total knee replacement. Total venous thromboembolism rates did not differ according to type of anaesthesia.
CONCLUSION: Although no issues were observed with the use of neuraxial anaesthesia in this population of 4086 patients receiving rivaroxaban after total hip or knee replacement, it is important to remain aware of the risk of compressive haematoma. This may be of particular concern in elderly patients with renal insufficiency receiving an anticoagulant predominantly eliminated via the kidneys.
Although venous thromboembolism has occasionally been reported after hospital discharge in patients who have undergone total hip replacement (THR), this risk has not been fully quantified and the usefulness of a prophylactic treatment has not been evaluated. We conducted a single-centre prospective randomised double-blind clinical trial in 2 parallel groups of patients who had undergone THR and were free of deep venous thrombosis (DVT) at discharge, as assessed by bilateral ascending venography. During hospitalisation, all patients received a low molecular weight heparin, enoxaparin (enoxaparin sodium), as a prophylactic treatment for venous thromboembolism. Just before hospital discharge (15 ± 1 days from surgery) 179 consecutive patients were randomly assigned to receive subcutaneous enoxaparin 40mg (n = 90) or placebo (n = 89) once daily for 21 ± 2 days. The primary efficacy outcome was defined as the occurrence of DVT and/or documented pulmonary embolism (PE). DVT was assessed by ascending bilateral venography performed 21 ± 2 days after randomisation or earlier if necessary. Secondary efficacy outcomes were the occurrence of proximal and distal DVT. Safety outcomes were defined as the occurrence of major and minor haemorrhage, other adverse events and changes in laboratory parameters. All patients underwent a 3-month follow-up. There were no deaths or cases of clinical PE during the study and the follow-up periods. In 173 patients with evaluable venograms, analysis of efficacy on an intention-to-treat basis showed that the incidence of DVT at day 21 was significantly lower in the enoxaparin group (6 of 85; 7.1%) than in the placebo group (17 of 88; 19.3%; p = 0.018), a risk reduction of 63%. Distal DVT was less frequent in the enoxaparin group than in the placebo group (1.2 vs 11.4%; p = 0.006) but there was no significant difference between groups in the incidence of proximal DVT. A ‘per-protocol’ analysis of efficacy in 155 patients confirmed the results for total and distal DVT, but also showed a trend in efficacy in favour of enoxaparin with regard to the incidence of proximal DVT (p = 0.064). En-oxaparin was safe in comparison with placebo: only 2 minor bleedings occurred in the enoxaparin group and there was no difference in the incidence of other adverse events between the 2 groups. In patients undergoing THR, the risk of late-occurring DVT remained high during the 21 days after hospital discharge in the placebo group. Prophylactic treatment with enoxaparin reduced the risk and was well tolerated in this context.
Stress-induced hyperglycaemia is common during orthopaedic surgery. In addition, hyperglycaemia activates coagulation. The aim of the study was to assess whether stress-induced hyperglycaemia is associated with symptomatic or asymptomatic venous thromboembolism (VTE) following orthopaedic surgery. We performed post-hoc analyses in the four RECORD studies (REgulation of Coagulation in major Orthopaedic surgery reducing the Risk of Deep venous thrombosis and pulmonary embolism). Separate analyses were performed for patients undergoing elective total hip or knee replacement. Outcome measures were symptomatic VTE and "total VTE" (defined as the composite of symptomatic VTE, asymptomatic DVT assessed by per protocol venography and all cause mortality). Glucose levels were measured pre-op and 6 hours post-op, categorised into quartiles, based on the distribution in the respective cohorts. The influence of glucose, adjusted for body mass index, age, gender and diabetes mellitus on VTE was assessed by logistic regression analyses. A total of 12,383 patients were eligible for assessment of symptomatic VTE, and 8,512 patients were eligible for assessment of total VTE. Increased glucose levels after total hip replacement were associated with total VTE; adjusted odds ratio (OR) highest versus lowest quartile 1.9 (95% confidence interval [CI] 1.3 to 3.0). Furthermore, increase in glucose levels during total hip replacement was associated with total VTE (OR highest versus lowest quartile 1.8 (95%CI 1.2 to 2.8). This was not observed in patients undergoing total knee replacement, probably due to differences in the applied surgical procedures.
INTRODUCTION: The RECORD programme compared oral rivaroxaban with enoxaparin for prevention of venous thromboembolism after elective total hip or knee replacement. This analysis compared the safety of concomitant use of specified medications with rivaroxaban and enoxaparin by evaluating postoperative bleeding rates from the pooled RECORD1-4 data.
MATERIALS AND METHODS: The co-medications were non-steroidal anti-inflammatory drugs and platelet function inhibitors, including acetylsalicylic acid (no dose restriction). The endpoints evaluated were the composite of major and non-major clinically relevant bleeding and any bleeding occurring after first oral study drug intake. The time relative to surgery was stratified into three time periods: day 1-3, day 4-7 and after day 7. Relative bleeding rate ratios for co-medication use versus non-use were derived using stratified Mantel-Haenszel methods and compared between rivaroxaban and enoxaparin groups.
RESULTS: Co-medication use with rivaroxaban or enoxaparin resulted in non-significant increases in bleeding events. Respective rate ratios were not significantly different between rivaroxaban and enoxaparin for all bleeding endpoints with concomitant use of non-steroidal anti-inflammatory drugs (any bleeding, 1.22 vs 1.22; major and non-major clinically relevant bleeding, 1.28 vs 0.90) and with concomitant use of platelet function inhibitors/acetylsalicylic acid (any bleeding, 1.32 vs 1.40; major and non-major clinically relevant bleeding, 1.11 vs 1.13).
CONCLUSIONS: This explorative analysis indicates that there is no significant increase in bleeding risk for rivaroxaban compared with enoxaparin when co-administered with non-steroidal anti-inflammatory drugs or acetylsalicylic acid, although, because of low usage, the experience with platelet function inhibitors (except acetylsalicylic acid) was limited.
In order to compare the effect of oral apixaban (a factor Xa inhibitor) with subcutaneous enoxaparin on major venous thromboembolism and major and non-major clinically relevant bleeding after total knee and hip replacement, we conducted a pooled analysis of two previously reported double-blind randomised studies involving 8464 patients. One group received apixaban 2.5 mg twice daily (plus placebo injection) starting 12 to 24 hours after operation, and the other received enoxaparin subcutaneously once daily (and placebo tablets) starting 12 hours (± 3) pre-operatively. Each regimen was continued for 12 days (± 2) after knee and 35 days (± 3) after hip arthroplasty. All outcomes were centrally adjudicated. Major venous thromboembolism occurred in 23 of 3394 (0.7%) evaluable apixaban patients and in 51 of 3394 (1.5%) evaluable enoxaparin patients (risk difference, apixaban minus enoxaparin, -0.8% (95% confidence interval (CI) -1.2 to -0.3); two-sided p = 0.001 for superiority). Major bleeding occurred in 31 of 4174 (0.7%) apixaban patients and 32 of 4167 (0.8%) enoxaparin patients (risk difference -0.02% (95% CI -0.4 to 0.4)). Combined major and clinically relevant non-major bleeding occurred in 182 (4.4%) apixaban patients and 206 (4.9%) enoxaparin patients (risk difference -0.6% (95% CI -1.5 to 0.3)). Apixaban 2.5 mg twice daily is more effective than enoxaparin 40 mg once daily without increased bleeding.
Post-operative complications after total hip or knee replacement can delay recovery, prolong hospitalisation, increase rates of re-admission and, in the most severe cases, lead to long-term disability or even death. In this analysis of pooled data from four large, randomised, phase III clinical trials that compared the oral, direct Factor Xa inhibitor rivaroxaban with subcutaneous enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement (n = 12,729), the incidence of complications, including bleeding and adverse events related to surgery (such as wound infection, wound dehiscence and haemarthrosis) are reported. Interventions and procedures relating to surgery are also compared between the groups. Bleeding events, including excessive wound haematoma and surgical-site bleeding, occurred at similar rates in the rivaroxaban and enoxaparin groups. Over the total study duration, adverse surgical events occurred at a similar rate in the rivaroxaban group compared with the enoxaparin group after total knee replacement (2.26% vs. 2.69%, respectively) and total hip replacement (1.48% vs. 1.65%, respectively). Blood loss, wound drainage and transfusion requirements were also similar between the two groups. This analysis shows that the incidence of adverse surgical events with rivaroxaban was similar to enoxaparin.
Thromboprophylaxis for at least 10 days and for up to 4–5 weeks is recommended after total hip arthroplasty (THA). Rivaroxaban is an oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. RECORD1 was a phase III, multinational, randomized, double-blind, double-dummy trial, conducted to determine the efficacy and safety of oral rivaroxaban, compared with subcutaneous enoxaparin, for 5 weeks of thromboprophylaxis in patients undergoing THA.
METHODS:
Patients received rivaroxaban 10 mg beginning 6–8 hours after surgery and once daily (od) thereafter, or enoxaparin 40 mg od, beginning the evening before surgery (restarting 6–8 hours after surgery). Therapy continued for 35±4 days and mandatory, bilateral venography was conducted the next day. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality. The primary efficacy analysis was a test for non-inferiority in the per-protocol (PP) population, followed by a test for superiority in the modified intention-to-treat (mITT) population. The main secondary efficacy endpoint was major venous thromboembolism (VTE): the composite of proximal DVT, non-fatal PE and VTE-related death. Major and non-major bleeding during the active treatment period were the primary and secondary safety endpoints, respectively.
RESULTS:
A total of 4541 patients were randomized; 4433 were eligible for the safety population, 3153 for the mITT population, and 3029 for the PP population. The criteria for non-inferiority were met and testing for superiority was performed. Rivaroxaban significantly reduced the incidence of the primary efficacy endpoint (p<0.001) and major VTE (p<0.001), compared with enoxaparin, in the mITT population (Table). The incidence of major and non-major bleeding events was similar in both groups (Table).
CONCLUSIONS:
Rivaroxaban was significantly more effective than enoxaparin for extended prophylaxis after THA, with a similar safety profile. This is the first pivotal trial to demonstrate the efficacy and safety of a fixed, unmonitored dose of an oral, direct Factor Xa inhibitor - rivaroxaban - for extended thromboprophylaxis after THA.
