Rivaroxaban (xarelto) for the prevention of thromboembolic disease: an inside look at the oral direct factor xa inhibitor.

Thromboembolic disease is associated with significant mortality and morbidity, especially in hospitalized patients. Without thromboprophylaxis, the risk of deep-vein thrombosis (DVT) in hospitalized patients is 10% to 40% in medical and general surgical patients and 40% to 60% in patients undergoing orthopedic surgery.1 Adverse consequences of unrecognized, untreated, or inadequately treated venous thromboembolism (VTE) include an increased risk of symptomatic DVT or pulmonary embolism (PE), fatal PE, increased hospital expenditures, and an increased risk of chronic post-thrombotic syndrome.1 Prophylaxis and proper management with an appropriate anticoagulant can reduce these risks. Current pharmacological options for the management and prevention of VTE are associated with several limitations and produce their anticoagulation effects at various points in the coagulation cascade. Unfractionated heparin (UFH) indirectly inhibits factors IIa, IXa, Xa, XIa, and XIIa by forming a complex with antithrombin and initiating its activity. Low-molecular-weight heparins (LMWHs) inhibit thrombin generation by a mechanism similar to that of UFH, but they have a stronger affinity for factor Xa than for factor IIa. Limitations of UFH and LMWHs include their ability to induce immune-mediated platelet activation, which can lead to heparin-induced thrombocytopenia (HIT), the need for frequent laboratory monitoring (with UFH only), adverse effects on bone metabolism, and a potential for increased serum transaminases.2 Although GlaxoSmithKline’s anticoagulant fondaparinux (Arixtra) selectively inhibits factor Xa, antithrombin is required as a cofactor to produce its effect. Direct thrombin inhibitors, such as argatroban (GlaxoSmithKline), lepirudin (Refludan, Bayer), and bivalirudin (Angiomax, The Medicines Company), bind directly to thrombin to produce their effect. These agents have a narrow therapeutic index and a short half-life. They must be given as a continuous infusion, thereby making this an unreasonable option for outpatients.2 These agents are also expensive and are available only as injectables that must be administered parenterally. The only orally available agent for the long-term management of thromboembolic disease in the U.S. is warfarin (Coumadin, Bristol-Myers Squibb). Warfarin inhibits factors II, VII, IX, and X by blocking vitamin K–mediated carboxylation of their precursors.3 Although warfarin is effective in managing and preventing thromboembolic disease over time, its variable pharmacokinetics, its significant potential for drug interactions, its slow onset of effect, and a patient’s genetic factors contribute to its unpredictable response, thus requiring close monitoring for dose initiation and adjustments. Therefore, there is a need for a safe and effective anticoagulant with a predictable pharmacokinetic profile without the need for frequent laboratory monitoring. Factor Xa is generated via the intrinsic and extrinsic pathways and is the rate-limiting step in the propagation of thrombin generation. Studies with fondaparinux have shown that factor Xa inhibition provides effective thromboprophylaxis. Rivaroxaban (Xarelto, Bayer) is an oral direct factor Xa inhibitor currently being evaluated in phase 3 clinical trials. This article reviews the pharmacology, pharmacokinetics, clinical efficacy, and safety data for this agent.