Rivaroxaban or Enoxaparin in Nonmajor Orthopedic Surgery.

BACKGROUND: Nonmajor orthopedic surgery of the lower limbs that results in transient reduced mobility places patients at risk for venous thromboembolism. Rivaroxaban may be noninferior to enoxaparin with regard to the prevention of major venous thromboembolism in these patients. METHODS: In this international, parallel-group, randomized, double-blind, noninferiority trial, we randomly assigned adult patients undergoing lower-limb nonmajor orthopedic surgery who were considered to be at risk for venous thromboembolism on the basis of the investigator's judgment to receive either rivaroxaban or enoxaparin. The primary efficacy outcome of major venous thromboembolism was a composite of symptomatic distal or proximal deep-vein thrombosis, pulmonary embolism, or venous thromboembolism-related death during the treatment period or asymptomatic proximal deep-vein thrombosis at the end of treatment. A test for superiority was planned if rivaroxaban proved to be noninferior to enoxaparin. For all outcomes, multiple imputation was used to account for missing data. Prespecified safety outcomes included major bleeding (fatal, critical, or clinically overt bleeding or bleeding at the surgical site leading to intervention) and nonmajor clinically relevant bleeding. RESULTS: A total of 3604 patients underwent randomization; 1809 patients were assigned to receive rivaroxaban, and 1795 to receive enoxaparin. Major venous thromboembolism occurred in 4 of 1661 patients (0.2%) in the rivaroxaban group and in 18 of 1640 patients (1.1%) in the enoxaparin group (risk ratio with multiple imputation, 0.25; 95% confidence interval, 0.09 to 0.75; P<0.001 for noninferiority; P = 0.01 for superiority). The incidence of bleeding did not differ significantly between the rivaroxaban group and the enoxaparin group (1.1% and 1.0%, respectively, for major bleeding or nonmajor clinically relevant bleeding; 0.6% and 0.7%, respectively, for major bleeding). CONCLUSIONS: Rivaroxaban was more effective than enoxaparin in the prevention of venous thromboembolic events during a period of immobilization after nonmajor orthopedic surgery of the lower limbs. (Funded by Centre Hospitalier Universitaire de Saint-Etienne and Bayer; PRONOMOS ClinicalTrials.gov number, NCT02401594.).

[Perioperative anticoagulation with NOAC using the example of rivaroxaban]. / Perioperative Antikoagulation mit NOAK am Beispiel Rivaroxaban.

BACKGROUND: Recent findings require an update of earlier recommendations on the perioperative management of non Vitamin K antagonist oral anticoagulants (NOAC). METHOD: The present position paper summarises the outcomes of an expert panel discussion. RESULTS AND CONCLUSIONS: Based on the pharmacokinetic profile of rivaroxaban, a preoperative interruption of 24-72 hours is recommended depending on the patient's renal function, as well as individual and surgery-related bleeding risks. Similar NOAC-free intervals are recommended for patients with epidural catheters. Elective surgery should be delayed accordingly. A low molecular weight heparin (LMWH) "bridging" (in fact "switching") should be avoided because of an increased bleeding risk. Six to 8 hours after the intervention rivaroxaban can be re-initiated or, in case of more extensive interventions or an increased bleeding risk, after 24-72 hours; if necessary this interval could by bridged with LMWH, e. g. if the thromboembolic risk is considered high. In case of emergency surgery with a rivaroxaban pause of less than 9 hours, one should be prepared for a bleeding management including the use of prothrombin concentrate (PCC). Coagulation tests have no value for predicting perioperative bleeding, in contrast to a standardised bleeding history. As an overall estimate, the PT (Quick) can be determined with a suitable reagent. Currently, rivaroxaban-specific measurements of anti Xa levels are available at few specialised centres only. Moderate to severe haemorrhages can usually be managed by temporary interruption of rivaroxaban in conjunction with local and general haemostatic measures. Life-threatening bleeding events require a specific haemostasis management including the administration of PCC; these events are rare and usually have a favourable prognosis, except for intracranial haemorrhages.

Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer.

BACKGROUND: Patients receiving chemotherapy for cancer are at increased risk for venous thromboembolism. Limited data support the clinical benefit of antithrombotic prophylaxis. METHODS: In this double-blind, multicenter trial, we evaluated the efficacy and safety of the ultra-low-molecular-weight heparin semuloparin for prevention of venous thromboembolism in patients receiving chemotherapy for cancer. Patients with metastatic or locally advanced solid tumors who were beginning to receive a course of chemotherapy were randomly assigned to receive subcutaneous semuloparin, 20 mg once daily, or placebo until there was a change of chemotherapy regimen. The primary efficacy outcome was the composite of any symptomatic deep-vein thrombosis, any nonfatal pulmonary embolism, and death related to venous thromboembolism. Clinically relevant bleeding (major and nonmajor) was the main safety outcome. RESULTS: The median treatment duration was 3.5 months. Venous thromboembolism occurred in 20 of 1608 patients (1.2%) receiving semuloparin, as compared with 55 of 1604 (3.4%) receiving placebo (hazard ratio, 0.36; 95% confidence interval [CI], 0.21 to 0.60; P<0.001), with consistent efficacy among subgroups defined according to the origin and stage of cancer and the baseline risk of venous thromboembolism. The incidence of clinically relevant bleeding was 2.8% and 2.0% in the semuloparin and placebo groups, respectively (hazard ratio, 1.40; 95% CI, 0.89 to 2.21). Major bleeding occurred in 19 of 1589 patients (1.2%) receiving semuloparin and 18 of 1583 (1.1%) receiving placebo (hazard ratio, 1.05; 95% CI, 0.55 to 1.99). Incidences of all other adverse events were similar in the two study groups. CONCLUSIONS: Semuloparin reduces the incidence of thromboembolic events in patients receiving chemotherapy for cancer, with no apparent increase in major bleeding. (Funded by Sanofi; ClinicalTrials.gov number, NCT00694382.).

Preoperative enoxaparin versus postoperative semuloparin thromboprophylaxis in major abdominal surgery: a randomized controlled trial.

OBJECTIVE: To compare efficacy and safety of thromboprophylaxis with semuloparin started postoperatively versus enoxaparin started preoperatively in major abdominal surgery. BACKGROUND: Venous thromboembolism is an important complication following major abdominal surgery. Semuloparin is a novel ultra-low-molecular-weight heparin with high antifactor Xa and minimal antifactor IIa activity. METHODS: In this double-blind noninferiority trial, adult patients undergoing major abdominal or pelvic operation under general anesthesia lasting more than 45 minutes were assigned to either daily enoxaparin 40 mg commenced preoperatively or daily semuloparin 20 mg commenced postoperatively, for 7 to 10 days. Patients underwent bilateral leg venography between 7 and 11 days postsurgery. The primary efficacy end point was the composite of any deep vein thrombosis, nonfatal pulmonary embolism, or all-cause death. The primary safety outcome was bleeding. Both were independently adjudicated. RESULTS: In total, 4413 patients were randomized; 3030 (1499 in the enoxaparin and 1531 in the semuloparin groups) were evaluable for the primary efficacy end point, which occurred in 97 patients (6.3%) in the semuloparin group and 82 patients (5.5%) in the enoxaparin group [odds ratio (OR) = 1.16, 95% confidence interval (CI): 0.84-1.59]. On the basis of a noninferiority margin of 1.25, postoperative semuloparin did not demonstrate noninferiority to preoperative enoxaparin. Major bleeding occurred in 63 of 2175 patients (2.9%) in the semuloparin group and 98 of 2177 patients (4.5%) in the enoxaparin group (OR = 0.63, 95% CI: 0.46-0.87). CONCLUSIONS: Semuloparin commenced postoperatively did not demonstrate noninferiority to enoxaparin initiated preoperatively for thromboprophylaxis after major abdominal surgery. Study registered with clinicaltrials.gov: NCT00679588.

Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial.

BACKGROUND: The risk of venous thromboembolism is high after total hip arthroplasty and could persist after hospital discharge. Our aim was to compare the use of rivaroxaban for extended thromboprophylaxis with short-term thromboprophylaxis with enoxaparin. METHODS: 2509 patients scheduled to undergo elective total hip arthroplasty were randomly assigned, stratified according to centre, with a computer-generated randomisation code, to receive oral rivaroxaban 10 mg once daily for 31-39 days (with placebo injection for 10-14 days; n=1252), or enoxaparin 40 mg once daily subcutaneously for 10-14 days (with placebo tablet for 31-39 days; n=1257). The primary efficacy outcome was the composite of deep-vein thrombosis (symptomatic or asymptomatic detected by mandatory, bilateral venography), non-fatal pulmonary embolism, and all-cause mortality up to day 30-42. Analyses were done in the modified intention-to-treat population, which consisted of all patients who had received at least one dose of study medication, had undergone planned surgery, and had adequate assessment of thromboembolism. This study is registered at ClinicalTrials.gov, number NCT00332020. FINDINGS: The modified intention-to-treat population for the analysis of the primary efficacy outcome consisted of 864 patients in the rivaroxaban group and 869 in the enoxaparin group. The primary outcome occurred in 17 (2.0%) patients in the rivaroxaban group, compared with 81 (9.3%) in the enoxaparin group (absolute risk reduction 7.3%, 95% CI 5.2-9.4; p<0.0001). The incidence of any on-treatment bleeding was much the same in both groups (81 [6.6%] events in 1228 patients in the rivaroxaban safety population vs 68 [5.5%] of 1229 patients in the enoxaparin safety population; p=0.25). INTERPRETATION: Extended thromboprophylaxis with rivaroxaban was significantly more effective than short-term enoxaparin plus placebo for the prevention of venous thromboembolism, including symptomatic events, in patients undergoing total hip arthroplasty.

Rivaroxaban for venous thromboembolism prevention after major orthopedic surgery: translating trial data into routine clinical practice.

An established standard of care for the prevention of venous thromboembolism after major orthopedic surgery has been subcutaneous low-molecular-weight heparin. The non-vitamin K antagonist oral anticoagulant rivaroxaban has demonstrated superior efficacy and similar safety to all tested regimens of enoxaparin in large Phase III clinical studies of venous thromboembolism prevention after elective hip and knee arthroplasty. Despite regulatory approval of rivaroxaban for this indication, concerns remain among physicians regarding its optimal and effective use in routine clinical practice. Real-life studies, such as XAMOS and ORTHO-TEP, are providing physicians with more information on the routine use of rivaroxaban for venous thromboembolism prevention after orthopedic surgery, helping to establish its safety and effectiveness in everyday clinical care. Among the most important issues are the risk of bleeding complications, wound healing, timing of first dose, impact of type of anesthesia on thromboprophylaxis effectiveness, patient comorbidities and comedication use, periprocedural management, associated costs, and clinical outcomes in trauma-related fractures. Many of these issues are difficult to study in randomized, double-blind, Phase III trials, and can be assessed more readily using real-life data. In particular, real-life or noninterventional studies lack many of the strict inclusion and exclusion criteria associated with Phase III trials and involve unselected patients who often present with significant comorbidities or comedication use.

[Rivaroxaban for thrombosis prophylaxis in extensive hip and knee operations. Subanalysis of the German cohort (XAMOS-DE) of non-interventional study XAMOS]. / Rivaroxaban in der Thromboseprophylaxe bei großen Hüft- und Knieoperationen : Subanalyse der deutschen Kohorte der nicht interventionellen XAMOS-Studie.

BACKGROUND: In global admission studies (RECORD I-IV) Rivaroxaban and enoxaparin as a standard prophylaxis were comparable in safety of treatment, but rivaroxaban appeared more effective in prevention of venous thromboembolism (VTE) when used in elective hip and knee replacement. The worldwide non-interventional cohort study XAMOS confirmed these results in the clinical routine compared to proven anticoagulants. METHOD: Efficacy and safety of rivaroxaban was to be compared with the standard prophylaxis in the prevention of VTE after elective hip and knee replacement surgery in clinical practice in Germany. For this purpose a subanalysis of the 2,719 patients (XAMOS-DE) included in XAMOS in German study centers was performed. RESULTS: Out of 2,719 patients in 32 study centers 1,333 patients obtained rivaroxaban and 1,386 patients obtained standard prophylaxis. The incidence of symptomatic VTE-events (0.9% with rivaroxaban vs. 1.1% with standard prophylaxis) and severe bleeding by RECORD (0.5% vs. 0.9%) and EMA criteria (2.9 % vs. 3.0%) was similar in both groups. Most of the patients treated with rivaroxaban rated tolerability as "very good" and therapy as "very patient-friendly". CONCLUSION: The results from XAMOS-DE confirm in clinical practice the favorable benefit-risk ratio of rivaroxaban, as well as the current S3 guidelines for thromboembolism prophylaxis with rivaroxaban in elective hip and knee replacement.

Postoperative Melagatran/Ximelagatran for the Prevention of Venous Thromboembolism following Major Elective Orthopaedic Surgery : Effects of Timing of First Dose and Risk Factors for Thromboembolism and Bleeding Complications on Efficacy and Safety.

OBJECTIVES: To examine the influence of timing of postoperative initiation of subcutaneous melagatran followed by oral ximelagatran, and of risk factors for venous thromboembolism (VTE; including deep vein thrombosis [DVT] and pulmonary embolism [PE]) and bleeding complications, on the efficacy and safety of this regimen, compared with preoperative enoxaparin sodium, following total hip replacement (THR) or total knee replacement (TKR) surgery. DESIGN: Statistical analyses of efficacy and safety in subgroups of the METHRO III intention-to-treat population. MAIN OUTCOME MEASURES: Main efficacy outcome measures were major VTE (proximal DVT, PE or VTE-related death) and total VTE (distal or proximal DVT, fatal or non-fatal PE). The main safety outcome measures were blood transfusion, severe bleeding events, blood loss, bleeding-related adverse events and need for reoperation. RESULTS: In the combined THR and TKR population, melagatran initiated 4 - <8 hours postoperatively was non-inferior to enoxaparin sodium with respect to the risks of total VTE (absolute risk reduction [ARR] 0; 95% confidence interval [CI] -4.4, 4.4) and major VTE (ARR -0.63; 95% CI -2.94, 1.67). The rate of major VTE was unaffected by the different risk factors. In the combined THR and TKR population, blood transfusion requirements were lower with melagatran/ximelagatran than enoxaparin sodium (odds ratio 0.83; 95% CI 0.71, 0.96; p = 0.016). CONCLUSIONS: Melagatran/ximelagatran initiated 4 - <8 hours postoperatively provided a comparable level of protection against total and major VTE to preoperative enoxaparin sodium. Major VTE rates and safety were consistent across different patient subgroups. Subcutaneous melagatran followed by fixed-dose oral ximelagatran offers an alternative to the standard European low molecular-weight heparin regimen in a wide range of patients.

Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement.

We evaluated whether a postoperative regimen with melagatran followed by oral ximelagatran, two new direct thrombin inhibitors, was an optimal regimen for thromboprophylaxis in major orthopaedic surgery. In a double-blind study, 2788 patients undergoing total hip or knee replacement were randomly assigned to receive for 8 to 11 days either 3 mg of subcutaneous melagatran started 4-12 h postoperatively, followed by 24 mg of oral ximelagatran twice-daily or 40 mg of subcutaneous enoxaparin once-daily, started 12 h preoperatively. Ximelagatran was to be initiated within the first two postoperative days. The primary efficacy endpoint was venous thromboembolism (deep-vein thrombosis detected by mandatory venography, pulmonary embolism or unexplained death). The main safety endpoint was bleeding. Venous thromboembolism occurred in 355/1146 (31.0%) and 306/1122 (27.3%) patients in the ximelagatran and enoxaparin group, respectively, a difference in risk of 3.7% in favour of enoxaparin (p = 0.053). Bleeding was comparable between the two groups.

Assessment of bleeding after concomitant administration of antiplatelet and anticoagulant agents in lower limb arthroplasty.

In an analysis of the Melagatran Thrombosis Prophylaxis in Orthopedic Surgery (METHRO) III study, we evaluated whether concomitant administration of aspirin (ASA) and non-steroidal anti-inflammatory drugs (NSAIDs) with the direct thrombin inhibitor melagatran/ximelagatran or the low-molecular-weight heparin enoxaparin increased bleeding in patients undergoing major joint surgery. Further objectives were to compare the influence of the timing of initial postoperative administration of melagatran/ximelagatran on bleeding in orthopedic patients receiving ASA/NSAIDs and in comparison with the preoperative administration of enoxaparin. ASA or NSAIDs in conjunction with melagatran/ximelagatran or enoxaparin did not increase bleeding. Bleeding rates were not significantly different, irrespective of the timing of the initial postoperative dose of melagatran/ximelagatran (4-8 vs. 4-12 h) when compared with preoperative (12 h) administration of enoxaparin. Transfusion rates were significantly lower with administration of melagatran/ximelagatran compared with enoxaparin.

Ximelagatran for the prevention of venous thromboembolism following elective hip or knee replacement surgery.

Patients undergoing major lower-extremity orthopedic surgery such as total hip replacement (THR) and total knee replacement (TKR) are at an increased risk of venous thromboembolism (VTE). Routine prophylaxis is necessary to reduce the risk of deep vein thrombosis (DVT), which may progress to potentially fatal pulmonary embolism and secondary complications such as postthrombotic syndrome, recurrent DVT, and chronic pulmonary hypertension. Prophylaxis in patients undergoing TKR, THR, and hip fracture surgery is now standard practice and generally involves anticoagulant treatment with either low-molecular-weight heparin (LMWH) or warfarin for a period of 7 to 10 days, with extended prophylaxis in those with ongoing risk factors such as obesity, cancer, or previous VTE. Data from clinical practice suggest that there is a general trend toward longer postsurgical prophylaxis and shorter hospital stays, making practicality of treatment an important consideration. LMWH is effective for the prophylaxis of VTE, but the parenteral route of administration is not convenient for use in the outpatient setting. Warfarin, on the other hand, can be administered orally but requires the infrastructure for careful patient monitoring and dose adjustments because of its unpredictable dose-response relationship. The development of new anticoagulants has been pursued with the aim of improving efficacy, predictability, consistency of response, safety, and convenience. A recently approved anticoagulant, fondaparinux, has been proven to provide superior efficacy for the prevention of VTE compared with LMWH, but this agent requires parenteral administration and does not overcome the convenience issue. Ximelagatran is the oral form of the direct thrombin inhibitor melagatran, which is available for subcutaneous administration. Ximelagatran has a consistent anticoagulant response allowing fixed oral dosing without the need for coagulation monitoring. The efficacy and safety profile of melagatran/ximelagatran prophylaxis for VTE following THR and TKR has compared favorably with standard LMWH prophylaxis, as seen in the European METHRO II and III trials and EXPRESS trial, and with warfarin prophylaxis, as seen in the North American EXULT A and B trials. Several prophylactic treatment regimens have been evaluated in the European trials to determine the optimal dosing and timing of first dose of melagatran to achieve the best balance of efficacy and safety. Preoperative initiation of melagatran was more effective than when prophylactic treatment was initiated postoperatively, and the lowest rates of bleeding were associated with a postoperative initiation of prophylaxis. Early administration of the first postoperative melagatran dose (4 to 8 hours) was also associated with better prophylactic efficacy relative to a later postoperative start (8 to 12 hours). The results of the comprehensive international clinical trial program and in particular the optimal balance of efficacy/safety data provided by the METHRO III study have led to approval of melagatran/ximelagatran in 2004 in the European Union for the prevention of VTE in patients undergoing elective hip or knee replacement surgery. Ximelagatran has the potential to maximize the use of anticoagulation in patients discharged following major lower-extremity orthopedic surgery.