Louis M. Kwong

Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial

BACKGROUND Prophylaxis for venous thromboembolism is recommended for at least 10 days after total knee arthroplasty; oral regimens could enable shorter hospital stays. We aimed to test the efficacy and safety of oral rivaroxaban for the prevention of venous thromboembolism after total knee arthroplasty. METHODS In a randomised, double-blind, phase III study, 3148 patients undergoing knee arthroplasty received either oral rivaroxaban 10 mg once daily, beginning 6-8 h after surgery, or subcutaneous enoxaparin 30 mg every 12 h, starting 12-24 h after surgery. Patients had mandatory bilateral venography between days 11 and 15. The primary efficacy outcome was the composite of any deep-vein thrombosis, non-fatal pulmonary embolism, or death from any cause up to day 17 after surgery. Efficacy was assessed as non-inferiority of rivaroxaban compared with enoxaparin in the per-protocol population (absolute non-inferiority limit -4%); if non-inferiority was shown, we assessed whether rivaroxaban had superior efficacy in the modified intention-to-treat population. The primary safety outcome was major bleeding. This trial is registered with ClinicalTrials.gov, number NCT00362232. FINDINGS The primary efficacy outcome occurred in 67 (6.9%) of 965 patients given rivaroxaban and in 97 (10.1%) of 959 given enoxaparin (absolute risk reduction 3.19%, 95% CI 0.71-5.67; p=0.0118). Ten (0.7%) of 1526 patients given rivaroxaban and four (0.3%) of 1508 given enoxaparin had major bleeding (p=0.1096). INTERPRETATION Oral rivaroxaban 10 mg once daily for 10-14 days was significantly superior to subcutaneous enoxaparin 30 mg given every 12 h for the prevention of venous thromboembolism after total knee arthroplasty. FUNDING Bayer Schering Pharma AG, Johnson & Johnson Pharmaceutical Research & Development.

BAY 59-7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study.

Summary.  Background: BAY 59‐7939, a novel, oral, direct factor Xa inhibitor, is in clinical development for the prevention of venous thromboembolism (VTE), a frequent complication following orthopaedic surgery. Methods: In a multicenter, parallel‐group, double‐blind, double‐dummy study, 621 patients undergoing elective total knee replacement were randomly assigned to oral BAY 59‐7939 (2.5, 5, 10, 20, and 30 mg b.i.d., initiated 6–8 h postsurgery), or subcutaneous enoxaparin (30 mg b.i.d., initiated 12–24 h postsurgery). Treatment was continued until mandatory bilateral venography 5–9 days after surgery. The primary efficacy endpoint was a composite of any deep vein thrombosis (proximal and/or distal), confirmed non‐fatal pulmonary embolism and all‐cause mortality during treatment. The primary safety endpoint was major, postoperative bleeding during treatment. Results: Of the 613 patients treated, 366 (59.7%) were evaluable for the primary efficacy analysis. The primary efficacy endpoint occurred in 31.7%, 40.4%, 23.3%, 35.1%, and 25.4% of patients receiving 2.5, 5, 10, 20 and 30 mg b.i.d. doses of BAY 59‐7939, respectively (test for trend, P = 0.29), compared with 44.3% in the enoxaparin group. The frequency of major, postoperative bleeding increased with increasing doses of BAY 59‐7939 (test for trend, P = 0.0007), with no significant difference between any dose group compared with enoxaparin. Bleeding endpoints were lower for the 2.5–10 mg b.i.d. doses compared with higher doses of BAY 59‐7939. Conclusions: Oral administration of 2.5–10 mg b.i.d. of BAY 59‐7939, early in the postoperative period, showed potential efficacy and an acceptable safety profile, similar to enoxaparin, for the prevention of VTE in patients undergoing elective total knee replacement.

Population pharmacokinetics and pharmacodynamics of rivaroxaban - An oral, direct factor Xa inhibitor in patients undergoing major orthopaedic surgery

AbstractBackground: There is a clinical need for novel oral anticoagulants with predictable pharmacokinetics and pharmacodynamics. Rivaroxaban is an oral direct Factor Xa (FXa) inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. This analysis was performed to characterize the population pharmacokinetics and pharmacodynamics of rivaroxaban in patients participating in two phase II, double-blind, randomized, active-comparator-controlled studies of twice-daily rivaroxaban for the prevention of venous thromboembolism after total hip- or knee-replacement surgery. Methods: Sparse blood samples were taken from all patients participating in the studies (n = 1009). In addition, a subset of patients in the hip study (n = 36) underwent full profiling. Rivaroxaban plasma concentrations, FXa activity and the prothrombin time were determined. Nonlinear mixed-effects modelling was used to model the population pharmacokinetics and pharmacodynamics of rivaroxaban. Results: An oral one-compartment model described the population pharmacokinetics of rivaroxaban well. On the first postoperative day only, categorization of patients as slow or fast absorbers as a tool to address variability in absorption improved the fit of the model. Clearance of rivaroxaban was lower and more variable on the first postoperative day, and so time was factored into the model. Overall, the only major difference between the models for the hip study and the knee study was that clearance was 26% lower in the knee study, resulting in approximately 30% higher exposure. Residual variability in the models was moderate (37% and 34% in the hip and knee studies, respectively). Plasma concentrations of rivaroxaban increased dose dependently. Pharmacokinetic parameters that were estimated using the models agreed closely with results from full-profile patients in the hip study, demonstrating that rivaroxaban pharmacokinetics are predictable. The pharmacokinetics of rivaroxaban were affected by expected covariates: age affected clearance in the hip study only, haematocrit (on the first postoperative day only) and gender affected clearance in the knee study only, and renal function affected clearance in both studies. Bodyweight affected the volume of distribution in both studies. However, the effects of covariates on the pharmacokinetics of rivaroxaban were generally small, and predictions of ‘extreme’ case scenarios suggested that fixed dosing of rivaroxaban was likely to be possible. FXa activity and the prothrombin time were both affected by surgery, probably because of perioperative bleeding and intravenous administration of fluids; therefore, time was included in the pharmacodynamic models. In both studies, FXa activity correlated with rivaroxaban plasma concentrations following a maximum effect model, whereas prothrombin time prolongation correlated following a linear model with intercept. The slope of the prothrombin time prolongation correlation was 3.2 seconds/(100 μg/L) in the hip study and 4.2 seconds/(100 μg/L) in the knee study. Both pharmacodynamic models in both studies demonstrated low residual variability of approximately 10%. Conclusion: This population analysis in patients undergoing major orthopaedic surgery demonstrated that rivaroxaban has predictable, dose-dependent pharmacokinetics that were well described by an oral one-compartment model and affected by expected covariates. Rivaroxaban exposure could be assessed using the prothrombin time, if necessary, but not the international normalized ratio. The findings suggested that fixed dosing of rivaroxaban may be possible in patients undergoing major orthopaedic surgery.

Rivaroxaban for thromboprophylaxis after orthopaedic surgery: pooled analysis of two studies.

Rivaroxaban (BAY 59-7939) is an oral, direct factor Xa inhibitor in clinical development for the prevention and treatment of venous thromboembolism (VTE). This analysis of pooled results from two phase II studies of rivaroxaban for VTE prevention after major orthopaedic surgery aimed to strengthen the conclusions of the individual studies. One study was conducted in patients undergoing total hip replacement (THR; N = 722), and one in patients undergoing total knee replacement (TKR; N = 621). In both studies, patients were randomized, doubleblind, to oral, twice-daily (bid) rivaroxaban beginning after surgery, or subcutaneous enoxaparin (40 mg once daily beginning before THR, and 30 mg bid beginning after TKR). Treatment continued until mandatory bilateral venography was performed 5-9 days after surgery. Total VTE (deep vein thrombosis, pulmonary embolism, and all-cause mortality) occurred in 16.1-24.4% of per-protocol patients receiving rivaroxaban 5-60 mg, and 27.8% receiving enoxaparin (n = 914). There was a flat dose response relationship between rivaroxaban and total VTE (p = 0.39). Major bleeding (safety population, n = 1,317) increased dose-dependently with rivaroxaban (p < 0.001), occurring in 0.9%, 1.3%, 2.1%, 3.9%, and 7.0% of patients receiving rivaroxaban total daily doses of 5, 10, 20, 40, and 60 mg, respectively, versus 1.7% of patients receiving enoxaparin. No routine coagulation monitoring was performed, and there were no significant differences between dose response relationships with rivaroxaban after THR and TKR. Overall, rivaroxaban total daily doses of 5-20 mg had the most favorable balance of efficacy and safety, relative to enoxaparin, for the prevention of VTE after major orthopaedic surgery.

Clinical and cost outcomes of venous thromboembolism in Medicare patients undergoing total hip replacement or total knee replacement surgery

Abstract Background: Venous thromboembolism (VTE) occurs most often during hospitalization for major surgery or trauma but may also occur up to several months after surgery. Since the potential for VTE exists in a range of clinical settings, an assessment of its impact on overall outcomes and costs to the patient and to the healthcare system is warranted. Objective: To evaluate the effects of VTE (deep vein thrombosis, pulmonary embolism, or both) occurring within the first 30 days of hospital discharge for total hip replacement (THR) or total knee replacement (TKR) surgery on inpatient costs, mortality, rehospitalization, and major bleeding within 1 year after initial hospitalization for THR or TKR surgery. Methods: The Medicare Provider Analysis and Review (MEDPAR) file for calendar years 2005–2007 provided hospital discharge abstracts for the fee-for-service, acute-care hospitalizations of all Medicare recipients. All patients included in the analysis underwent THR (n = 51,108) or TKR (n = 115,627). VTE events were diagnosed within the first 30 days and within 1 year post discharge. Propensity score matching was used to control for differences in baseline characteristics in patients with and without VTE events. Total cost was measured as Medicare cost plus beneficiary out-of-pocket cost. Results: VTE occurred in 0.74% of patients undergoing THR. For patients with VTE versus no VTE, mortality was higher (2.9% vs 0.4%, P < 0.001) and rehospitalization within 1 year was more frequent (51.9% vs 22.4%, P < 0.001), as were complications such as bleeding (11.2% vs 2.7%, P < 0.001). Risk-adjusted Medicare cost and total healthcare cost, including beneficiary cost share in 1 year, were significantly higher for VTE patients versus patients with no VTE (

Prevention of venous thromboembolism after hip or knee arthroplasty: findings from a 2008 survey of US orthopedic surgeons

18,929 vs

Drug Interactions with Rivaroxaban following Total Joint Replacement Surgery

3763, P < 0.001). VTE occurred in 0.70% of patients undergoing TKR. For patients with VTE versus no VTE, mortality was higher (2.5% vs 0.15%, P < 0.001), and rehospitalization within 1 year was more frequent (48.7% vs 20.7%, P < 0.001), as were complications such as bleeding (13.7% vs 2.1%, P < 0.001). For TKR surgery, risk-adjusted total healthcare cost, including beneficiary cost share in 1 year, was significantly different for VTE versus no VTE (

Opioid abuse-deterrent strategies: role of clinicians in acute pain management

17,996 vs

Real-world data confirm clinical trial outcomes for rivaroxaban in orthopaedic patients

4358, P < 0.001). Limitations: Study limitations include a reliance on ICD-9-CM codes, which could be inaccurate, and the inability (1) to control for unmeasured confounders, such as surgeons’ skills; (2) to include outpatient medical care costs; and (3) to ensure that all patients were enrolled continuously throughout the study period. Conclusions: VTE after THR or TKR is associated with higher mortality, rehospitalization, and bleeding within 1 year, compared with no VTE. Risk-adjusted total, Medicare, and beneficiary healthcare costs were significantly higher for both THR and TKR patients with VTE (P < 0.001).

Postorthopedic Surgery Joint Replacement Surgery Venous Thromboembolism Prophylaxis

A survey was mailed to a representative sample of US orthopedic surgeons to assess protocols for the prevention of venous thromboembolism after lower extremity total joint arthroplasty. Practices were examined by type of operation, annual surgical volume, and opinions of consensus guidelines issued by the American Academy of Orthopaedic Surgeons and the American College of Chest Physicians. Although there was near-unanimous agreement that routine thromboprophylaxis should be the standard practice for patients who undergo hip or knee arthroplasty, surgeons were divided as to the exact management approach.