Rivaroxaban: A Review of its Use for the Prevention of Venous Thromboembolism After Total Hip or Knee Replacement Surgery

• Published in: Drugs (New York, N.Y.) N.Y.), 2009-01, Vol.69 (13), p.1829-1851
• Main Authors: Duggan, Sean T., Scott, Lesley J., Plosker, Greg L.
• Format: Article
• Language: English
• Subjects: Adis Drug Evaluation; Animals; Anticoagulants (Medicine); Anticoagulants - adverse effects; Anticoagulants - economics; Anticoagulants - pharmacology; Anticoagulants - therapeutic use; Arthroplasty, Replacement, Hip - adverse effects; Arthroplasty, Replacement, Knee - adverse effects; Biological and medical sciences; Blood and lymphatic vessels; Blood. Blood coagulation. Reticuloendothelial system; Cardiology. Vascular system; Clinical Trials as Topic; Complications and side effects; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Dosage and administration; Drug therapy; Humans; Internal Medicine; Medical sciences; Medicine; Medicine & Public Health; Morpholines - adverse effects; Morpholines - economics; Morpholines - pharmacology; Morpholines - therapeutic use; Orthopedic surgery; Pharmacokinetics; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacotherapy; Risk factors; Rivaroxaban; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Thiophenes - adverse effects; Thiophenes - economics; Thiophenes - pharmacology; Thiophenes - therapeutic use; Thromboembolism; Venous Thromboembolism - etiology; Venous Thromboembolism - prevention & control
• ISSN: 0012-6667; 1179-1950
• DOI: 10.2165/11200890-000000000-00000

Summary Rivaroxaban (Xarelto®), an oral oxazolidinone-based anticoagulant, is a potent, selective direct inhibitor of factor Xa that is used in the prevention of venous thromboembolism (VTE) in adult patients after total hip replacement (THR) or total knee replacement (TKR) surgery. In four large, clinical trials, oral rivaroxaban was more effective than subcutaneous enoxaparin in preventing postoperative VTE in patients undergoing THR or TKR surgery. Notably, the superior efficacy of rivaroxaban was achieved with a low but not significant increase in the incidence of major bleeding episodes. In addition, preliminary pharmacoeconomic analyses in several countries indicate that rivaroxaban is a cost-effective treatment strategy versus enoxaparin. Although the position of rivaroxaban relative to other therapies remains to be fully determined, it is an effective emerging option for the prevention of VTE following THR and TKR. Pharmacological Properties Rivaroxaban is a potent oral direct inhibitor of the serine endopeptidase factor Xa and inhibits both free factor Xa and factor Xa bound in the prothrombinase complex. The potency of factor Xa inhibition occurs primarily as a result of rivaroxaban binding with high selectivity to the S1 and S4 pockets of the serine endopeptidase. In healthy volunteers and in orthopaedic surgery patients, rivaroxaban prophylaxis dose-dependently inhibited factor Xa and prolonged prothrombin (PT) and activated partial thromboplastin times confirming data from animal models. Plasma rivaroxaban concentrations correlated with both factor Xa inhibition and PT, following a maximum effect and linear model, respectively. Rivaroxaban prophylaxis did not prolong the corrected QT interval using the Fridericia formula. Rivaroxaban pharmacokinetics following oral administration are best described by a one-compartment model and are characterized by rapid absorption (peak plasma concentration reached within 2–4 hours) and high bioavailability (80–100%). The apparent volume of distribution of rivaroxaban at steady state is ≈50 L. Rivaroxaban can be classified as a low-clearance drug, with a mean apparent oral clearance rate in orthopaedic surgery patients of 5.5 L/h on the day of surgery, increasing to 7.5 L/h at steady state, and mean terminal half-life of between 7 and 11 hours. Approximately two-thirds of an administered rivaroxaban dose is metabolized via cytochrome P450 (CYP) enzymes (CYP3A4 and CYP2J2) and CYP-independent mechanisms, with