BACKGROUNDAlthough many patients with venous thromboembolism require extended treatment, it is uncertain whether it is better to use full-or lower-intensity anticoagulation therapy or aspirin. METHODSIn this randomized, double-blind, phase 3 study, we assigned 3396 patients with venous thromboembolism to receive either once-daily rivaroxaban (at doses of 20 mg or 10 mg) or 100 mg of aspirin. All the study patients had completed 6 to 12 months of anticoagulation therapy and were in equipoise regarding the need for continued anticoagulation. Study drugs were administered for up to 12 months. The primary efficacy outcome was symptomatic recurrent fatal or nonfatal venous thromboembolism, and the principal safety outcome was major bleeding. RESULTSA total of 3365 patients were included in the intention-to-treat analyses (median treatment duration, 351 days). The primary efficacy outcome occurred in 17 of 1107 patients (1.5%) receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients (4.4%) receiving aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P<0.001 for both comparisons). Rates of major bleeding were 0.5% in the group receiving 20 mg of rivaroxaban, 0.4% in the group receiving 10 mg of rivaroxaban, and 0.3% in the aspirin group; the rates of clinically relevant nonmajor bleeding were 2.7%, 2.0%, and 1.8%, respectively. The incidence of adverse events was similar in all three groups. CONCLUSIONSAmong patients with venous thromboembolism in equipoise for continued anticoagulation, the risk of a recurrent event was significantly lower with rivaroxaban at either a treatment dose (20 mg) or a prophylactic dose (10 mg) than with aspirin, without a significant increase in bleeding rates. (Funded by Bayer Pharmaceuticals; EINSTEIN CHOICE ClinicalTrials.gov number, NCT02064439.) a bs tr ac t

The rates of any infection, lower or upper respiratory tract and lung infection, and wound inflammation or infection were significantly increased after elective total hip or total knee arthroplasty in patients receiving allogeneic blood transfusion compared with those receiving autologous blood transfusion or no blood transfusion.

Rivaroxaban demonstrated superior efficacy and a similar safety profile to enoxaparin for the prevention of venous thromboembolism in the phase III RECORD programme in patients undergoing elective hip or knee replacement surgery. The XAMOS study investigated adverse events, including bleeding and thromboembolic events, in patients receiving rivaroxaban for thromboprophylaxis in routine clinical practice. XAMOS was a non-interventional, open-label cohort study in patients undergoing major orthopaedic surgery of the hip or knee (predominantly elective arthroplasty), in which rivaroxaban was compared with other pharmacological thromboprophylaxis. All adverse events were documented, including symptomatic thromboembolic and bleeding events. Crude and adjusted incidences based on propensity score subclasses were calculated and compared between the rivaroxaban and standard-of-care groups. A total of 17,701 patients were enrolled from 252 centres in 37 countries. Crude incidences of symptomatic thromboembolic events three months after surgery in the safety population were 0.89% in the rivaroxaban group (n=8,778) and 1.35% in the standard-of-care group (n=8,635; odds ratio [OR] 0.65; 95% confidence interval [CI] 0.49-0.87), and 0.91% and 1.31% (weighted) in the propensity score-adjusted analysis (OR 0.69; 95% CI 0.56-0.85), respectively. Treatment-emergent major bleeding events (as defined in the RECORD studies) occurred in 0.40% and 0.34% of patients in the rivaroxaban and standard-of-care groups in the safety population (OR 1.19; 95% CI 0.73-1.95), and in 0.44% versus 0.33% (weighted) in the propensity score-adjusted analysis (OR 1.35; 95% CI 0.94-1.93), respectively.This study in unselected patients confirmed the favourable benefit-risk profile of rivaroxaban seen in the RECORD programme.

AimThe aim of the present study was to analyse concomitant drug use and its association with outcome in patients (N = 17 701) receiving rivaroxaban or standard of care (SOC) for the prevention of venous thromboembolism after major orthopaedic surgery in the non‐interventional, phase IV XAMOS (Xarelto® in the prophylaxis of post‐surgical venous thromboembolism after elective major orthopaedic surgery of hip or knee) study.MethodsConcomitant drug use was at the discretion of the treating physician. Prespecified co‐medications of interest were cytochrome P450 (CYP) 3A4/P‐glycoprotein inhibitors/inducers, platelet aggregation inhibitors (PAIs) and nonsteroidal anti‐inflammatory drugs (NSAIDs). Crude event incidences were compared between rivaroxaban and SOC groups.ResultsCYP3A4/P‐glycoprotein inhibitor/inducer use was infrequent, in contrast to PAI (~7%) and NSAID (~52%) use. Rivaroxaban was associated with a lower incidence of overall symptomatic thromboembolic events compared with SOC, regardless of co‐medication use. In both treatment groups, PAI users, with higher age and prevalence of cardiovascular co‐morbidities, had similar higher (>7‐fold) incidences of symptomatic arterial but not venous thromboembolic events compared with non‐users. NSAID use had no influence on thromboembolic events. However, odds ratios (ORs) for major bleeding events (European Medicines Agency definition) were higher in NSAID users compared with non‐users in rivaroxaban [OR = 1.50; 95% confidence interval (CI) 1.06, 2.13] and SOC (OR = 1.70; CI 1.16, 2.49) groups. In PAI users, ORs for major bleeding events were no different from those of non‐users in both the rivaroxaban (OR = 1.49; CI 0.84, 2.65) and SOC (OR = 1.46; CI 0.82, 2.62) groups.ConclusionsUse of NSAIDs in XAMOS was frequent and associated with a higher frequency of bleeding events in patients receiving rivaroxaban or SOC, although the benefit–risk profile of rivaroxaban compared with SOC was maintained.

These data from routine practice demonstrate that rivaroxaban can provide effective thromboprophylaxis after fracture-related orthopedic surgery of the lower limb with a favorable safety profile.

Patients with unprovoked venous thromboembolism (VTE) are at high risk for recurrence. Although rivaroxaban is effective for extended VTE treatment at a dose of 20 mg once daily, use of the 10 mg dose may further improve its benefit-to-risk ratio. Low-dose aspirin also reduces rates of recurrent VTE, but has not been compared with anticoagulant therapy. The EINSTEIN CHOICE study is a multicentre, randomised, double-blind, active-controlled, event-driven study comparing the efficacy and safety of two once daily doses of rivaroxaban (20 and 10 mg) with aspirin (100 mg daily) for the prevention of recurrent VTE in patients who completed 6-12 months of anticoagulant therapy for their index acute VTE event. All treatments will be given for 12 months. The primary efficacy objective is to determine whether both doses of rivaroxaban are superior to aspirin for the prevention of symptomatic recurrent VTE, while the principal safety outcome is the incidence of major bleeding. The trial is anticipated to enrol 2,850 patients from 230 sites in 31 countries over a period of 27 months. In conclusion, the EINSTEIN CHOICE study will provide new insights into the optimal antithrombotic strategy for extended VTE treatment by comparing two doses of rivaroxaban with aspirin (clinicaltrials.gov NCT02064439).

500 Rivaroxaban for Thromboprophylaxis after Total Hip or Knee Replacement Surgery: Comparison of Outcomes of the XAMOS and RECORD Studies. Patients undergoing major orthopedic surgery are at risk of venous thromboembolism (VTE). Rivaroxaban has been approved for clinical use in this indication based on the extensive phase III RECORD program, which investigated the efficacy and safety of oral rivaroxaban regimens compared with subcutaneous enoxaparin regimens in patients undergoing elective total hip or knee replacement surgery. XAMOS is a phase IV, non-interventional, open-label cohort study that compared rivaroxaban with any pharmacological prophylaxis used in routine clinical practice for VTE prevention after major orthopedic surgery of the hip or knee. An additional aim of the XAMOS study was to assess whether the results from the phase III RECORD studies would be reflected in routine clinical practice. The XAMOS study, which ran from 2009 to 2011, collected data on the incidence of adverse events (including symptomatic thromboembolic and bleeding events) in adult patients from 252 centers in 37 countries worldwide, who underwent elective hip or knee replacement surgery (or hip fracture surgery, where appropriate) and received rivaroxaban or other pharmacological prophylaxis (standard of care). The attending physician determined the type, duration, and dose of drug. Of the 17,701 patients enrolled, 8778 received rivaroxaban and 8635 received standard of care, of whom 7055 (81.7%) received low molecular weight heparin (LMWH). Primary hip/knee replacement surgery accounted for >90% of all procedures. Baseline demographics (e.g. age, sex, body weight, and ethnicity) were similar for patients receiving rivaroxaban, standard of care, or LMWH, and were also similar to those of patients who received rivaroxaban in the RECORD program. LMWH was the comparator in the RECORD program; therefore, the XAMOS study also compared outcomes with LMWH and rivaroxaban. Data for the LMWH group were similar to the standard-of-care group. Rates of symptomatic arterial, venous, and all thromboembolic events in XAMOS were lower in the rivaroxaban group compared with the LMWH group (Figure 1). The data are consistent with the results of the RECORD1–4 pooled analysis, which showed a significantly lower incidence of symptomatic VTE and all-cause mortality in patients receiving rivaroxaban compared with those receiving enoxaparin (Figure 2). The rates of treatment-emergent major bleeding events (RECORD definition) were 0.4% vs 0.3% in the rivaroxaban and LMWH groups, respectively (odds ratio [OR]=1.28; 95% confidence interval [CI] 0.75–2.18; Figures 1 and 2), and were similar to those in the RECORD1–4 pooled analysis (day 12±2 active treatment pool: 0.3% [rivaroxaban] vs 0.2% [enoxaparin]; OR=1.62; 95% CI 0.77–3.53; Figure 2). When the European Medicines Agency (EMA) definition for treatment-emergent major bleeding was used, the incidence of major bleeding was slightly higher (nonsignificant) for patients receiving rivaroxaban compared with those receiving LMWH in the XAMOS study (1.7% vs 1.4%; OR=1.19; 95% CI: 0.92–1.53; Figures 1 and 2); these results were also similar to those of the RECORD1–4 pooled analysis (day 12±2 active treatment pool: 2.0% [rivaroxaban] vs 1.7% [enoxaparin]; OR=1.20; 95% CI: 0.91–1.57). XAMOS is the first study presenting real-world experience of the efficacy and safety of rivaroxaban for the prevention of VTE after major orthopedic surgery of the hip or knee. The results of XAMOS showed that rivaroxaban was associated with a significantly lower incidence of symptomatic VTE compared with LMWH, without a significant increase in the risk of major bleeding. These findings are consistent with those obtained in the RECORD studies, and indicate that the results of the RECORD program can be translated into the routine clinical setting. Disclosures: Turpie: GSK: Speakers Bureau; GSK, JnJ: Consultancy. Schmidt:Bayer: Employment, Equity Ownership. Lassen:Bayer: Speakers Bureau; Bristol-Myers Squibb; GlaxoSmithKline; Bayer; Boehringer: Consultancy; Sanofi-Aventis: Research Funding. Mantovani:Bayer Healthcare Pfizer Merck Serono Baxter Astellas: Speakers Bureau; Bayer Healthcare Pfizer Bristol-Meyer Squibb Amgen Merck&Co: Consultancy; Bayer Healthcare Pfizer Bristol-Meyer Squibb Biogen Idec Medtronic Admirall Otsuka Amgen Merck&Co Merck-Serono: Research Funding. Kreutz:Bristol-Myers Squibb, Bayerm Daichii Sankyo, Berlin-Chemie Menarini: Speakers Bureau; Bayer, Daichii Sankyo: financial and material support, financial and material support Other. Holberg:Bayer Healthcare: Employment. Haas:Sanofi Aventis: Speakers Bureau; Sanofi Aventis, Bristol-Myers Squibb: Consultancy.

PurposeReal-world data on the use of rivaroxaban in the perioperative period in patients undergoing major orthopedic surgery are limited. Subsets of data from the Phase IV, non-interventional XAMOS study were analyzed to explore the potential influence of timing of the first thrombo prophylactic dose, type of anesthesia, and concomitant mechanical prophylaxis on clinical outcomes in patients undergoing major orthopedic surgery in routine clinical practice.Patients and methodsIn XAMOS, 8,778 patients received rivaroxaban (10 mg once daily) and 8,635 received standard-of-care (SOC) pharmacological prophylaxis (safety population). Crude incidences of symptomatic thromboembolic and treatment-emergent bleeding events were analyzed according to timing of the first postoperative thromboprophylactic dose, use of general or neuraxial anesthesia, and use of mechanical prophylaxis with pharmacological thromboprophylaxis.ResultsIn the rivaroxaban group, the incidences of symptomatic thromboembolic events were 0.7%, 1.0%, and 0.7% in patients receiving the first thromboprophylactic dose at ≤6 hours, >6 hours to ≤10 hours, and >10 hours to ≤24 hours after surgery, respectively. In the SOC group, the incidence of symptomatic thromboembolic events was slightly higher when the postoperative dose was given at >10 hours to ≤24 hours (1.8% vs 1.1% at ≤6 hours and 1.3% at >6 hours to ≤10 hours). The antithrombotic effect of rivaroxaban was maintained in comparison to the SOC group. The incidence of major bleeding (RECORD trial definition) was low and similar between the two treatment groups and was not influenced by timing of the first thromboprophylactic dose. Neuraxial anesthesia was used more than any other form of anesthesia for both hip and knee surgery; the effectiveness of rivaroxaban was not influenced by the type of anesthesia used. No spinal hematomas were reported in patients receiving neuraxial anesthesia in either treatment group. Use of mechanical thromboprophylaxis in addition to rivaroxaban or SOC pharmacological prophylaxis did not reduce the risk of thromboembolic events further.ConclusionThe effectiveness and safety of rivaroxaban in patients undergoing major orthopedic surgery in routine clinical practice were maintained irrespective of timing of the first postoperative dose within 24 hours after surgery, the type of anesthesia, and the additional use of mechanical thromboprophylaxis.