Finding the Optimal Dose of Rivaroxaban in Hemodialysis Patients

1. Background and Rationale:

Vitamin K antagonists have been the standard anticoagulant treatment for decades, despite their unpredictable pharmacology and their slow onset and offset of action, requiring frequent monitoring and bridging with low molecular weight heparins (LMWH), and resulting in a substantial risk of under- and overtreatment. Patients with end-stage renal disease have an increased risk of bleeding due to their underlying disease. Therefore, anticoagulants need to be used with caution in these patients. In addition, the vitamin K antagonists are increasingly implicated in the development of vascular calcifications in this already vulnerable population. A search for alternative anticoagulants is therefore warranted.

Rivaroxaban is a recently developed factor Xa (FXa) inhibitor for the prevention and treatment of thromboembolic disease (1). Rivaroxaban has a much lower pharmacokinetic variability and little interaction with food and drugs, contributing to consistent and predictable anticoagulation. As a consequence, routine monitoring is not required. Rivaroxaban has been shown to be effective and safe in large trials on the prevention and treatment of venous thromboembolism (2,3) and the prevention of stroke in atrial fibrillation (4).

Rivaroxaban inhibits factor Xa in a concentration-dependent manner. Even though routine monitoring is not required, there are clinical situations in which an evaluation of its anticoagulant effect is desirable. Rivaroxaban prolongs prothrombin time (PT) and activated partial thromboplastin time (aPTTT) in a concentration-dependent manner. However, the extent of prolongation varies considerably with the type of reagent that is used. This variation cannot be reduced by conversion of PT values given in seconds to international normalized ratio values; therefore, PT and activated partial thromboplastin time are not useful for measuring the pharmacodynamic effects of rivaroxaban. Anti- Factor Xa activity is also influenced by rivaroxaban and is the most reliable method to evaluate the clinical effect of rivaroxaban (5).

The absolute bioavailability of rivaroxaban is high (80 % - 100 %) for the 10 mg dose, with maximum plasma concentration (Cmax). appearing 2 - 4 hours after tablet intake. Intake with food does not affect rivaroxaban area under the curve (AUC) or Cmax. Rivaroxaban pharmacokinetics are approximately linear up to about 15 mg once daily. Plasma protein binding in humans is high at approximately 92 % to 95 %, with serum albumin being the main binding component. Due to the high plasma protein binding rivaroxaban is not expected to be dialysable. There are, however, no data about plasma protein binding in hemodialysis patients. Unchanged rivaroxaban is the most important compound in human plasma, with no major or active circulating metabolites being present. With a systemic clearance of about 10 l/h, rivaroxaban can be classified as a low-clearance drug. After intravenous administration of a 1 mg dose the elimination half-life is about 4.5 hours. After oral administration of a 10 mg dose the elimination becomes absorption rate limited with mean terminal half-lives of 7 to 11 hours (6,7).