Extracorporeal Hemoperfusion as a Potential Therapeutic Option for Critical Accumulation of Rivaroxaban

Because of its efficacy, ease of dosing, and safety, the direct oral anticoagulant rivaroxaban is increasingly applied in a number of indications, for example, prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and treatment of deep vein thrombosis and pulmonary embolism. Median therapeutic peak plasma concentrations range from 46 to 270 µg/L, depending on the respective indication. However, there are concerns regarding the accumulation of the drug in patients with impaired renal clearance or in case of overdosing, potentially leading to an increased risk of bleeding. With its high degree of protein binding of 92–95%, rivaroxaban is regarded as non-dialyzable, as also suggested by results from a clinical study conducted by Dias et al.. Since protein binding is regarded as not a limiting factor in hemoperfusion, the removal of rivaroxaban, as for example by commonly available coated charcoal cartridges, has been deemed possible, but experimental evidence is still lacking. While Andexanet alfa may offer a promising approach to reverse the FXa inhibitor-mediated anticoagulation of rivaroxaban, it has not yet been approved. In case of rivaroxaban-related major bleeding events or emergency interventions with a high bleeding risk, therefore, a fast and effective countermeasure is urgently needed. Here, we present experimental work to remove rivaroxaban from the blood by means of hemoperfusion using an approved adsorption device (CytoSorb®; Cyto¬Sorbents Europe, Germany). Currently, CytoSorb is used mainly in patients with severe infections and sepsis (cytokine storm). We applied a model device containing 60 mL of the adsorbent polyvinylpyrrolidone-coated polystyrene-divinylbenzene copolymer in an in vitro recirculation system to remove high plasma concentrations of rivaroxaban (571 ± 20 µg/L) from citrate-anticoagulated human whole blood (1,000 mL, flow rate 40 mL/min) during 120 min of hemoperfusion (Fig. 1a). Molecules are captured on the internal pore surface of polystyrene-divinylbenzene by nonspecific hydrophobic interactions, whereby solutes with molecular weights equal to and larger than that of albumin, particularly clotting factors, are excluded from adsorption by adjustment of the pore size distribution.